Algal Research 57 (2021) 102331
Contents lists available at ScienceDirect
Algal Research
journal homepage: www.elsevier.com/locate/algal
Viral inhibitors derived from macroalgae, microalgae, and cyanobacteria: A
review of antiviral potential throughout pathogenesis
Daman Reynolds a, Michael Huesemann a, *, Scott Edmundson a, Amy Sims b, Brett Hurst c,
Sherry Cady a, 1, Nathan Beirne a, Jacob Freeman a, Adam Berger a, Song Gao a
a
b
c
Pacific Northwest National Laboratory, Marine and Coastal Research Laboratory, Sequim, WA, USA
Pacific Northwest National Laboratory, Chemical and Biological Signatures Group, Richland, WA, USA
Institute for Antiviral Research, Utah State University, Logan, UT, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Antiviral
Algae
Seaweed
SARS-CoV-2
COVID-19
Pathogenesis
Viral inhibitors
Prophylactic
Virucidal
Virustatic
Entry inhibitors
Enzyme inhibitors
Immunostimulants
Antioxidants
Viruses are abiotic obligate parasites utilizing complex mechanisms to hijack cellular machinery and reproduce,
causing multiple harmful effects in the process. Viruses represent a growing global health concern; at the time of
writing, COVID-19 has killed at least two million people around the world and devastated global economies.
Lingering concern regarding the virus' prevalence yet hampers return to normalcy. While catastrophic in and of
itself, COVID-19 further heralds in a new era of human-disease interaction characterized by the emergence of
novel viruses from natural sources with heretofore unseen frequency. Due to deforestation, population growth,
and climate change, we are encountering more viruses that can infect larger groups of people with greater ease
and increasingly severe outcomes. The devastation of COVID-19 and forecasts of future human/disease interactions call for a creative reconsideration of global response to infectious disease. There is an urgent need for
accessible, cost-effective antiviral (AV) drugs that can be mass-produced and widely distributed to large populations. Development of AV drugs should be informed by a thorough understanding of viral structure and
function as well as human biology. To maximize efficacy, minimize cost, and reduce development of drugresistance, these drugs would ideally operate through a varied set of mechanisms at multiple stages
throughout the course of infection. Due to their abundance and diversity, natural compounds are ideal for such
comprehensive therapeutic interventions. Promising sources of such drugs are found throughout nature; especially remarkable are the algae, a polyphyletic grouping of phototrophs that produce diverse bioactive compounds. While not much literature has been published on the subject, studies have shown that these compounds
exert antiviral effects at different stages of viral pathogenesis. In this review, we follow the course of viral
infection in the human body and evaluate the AV effects of algae-derived compounds at each stage. Specifically,
we examine the AV activities of algae-derived compounds at the entry of viruses into the body, transport through
the body via the lymph and blood, infection of target cells, and immune response. We discuss what is known
about algae-derived compounds that may interfere with the infection pathways of SARS-CoV-2; and review
which algae are promising sources for AV agents or AV precursors that, with further investigation, may yield lifesaving drugs due to their diversity of mechanisms and exceptional pharmaceutical potential.
1. Introduction
According to best estimates at the time of writing, at least 2.4 million
people have been killed by COVID-19 in >200 countries since January
2020 [1,2]. Owing to a lack of testing and overwhelmed healthcare
systems, it is likely that COVID-19's actual death toll is significantly
higher, especially in developing nations [3,4]. Global economies have
drastically declined, and tens of millions of people are at risk of dropping
down past the $1.90 income threshold of extreme deprivation [5,6]. In
addition to its catastrophic short-term effects, COVID-19 is a harbinger
of a growing global trend in infectious disease.
Widespread viral outbreaks will continue to challenge human civilization [7]. COVID-19 is caused by SARS-CoV-2, a zoonotic virus that
originated in an alternative animal host (potentially a horseshoe bat or
* Corresponding author.
E-mail address: Michael.huesemann@pnnl.gov (M. Huesemann).
1
Current address: Portland State University, Department of Geology/Center for Life in Extreme Environments, Portland, OR 97207
https://doi.org/10.1016/j.algal.2021.102331
Received 4 March 2021; Received in revised form 24 April 2021; Accepted 27 April 2021
Available online 18 May 2021
2211-9264/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
D. Reynolds et al.
Algal Research 57 (2021) 102331
pangolin) before spreading to humans [8]. It is estimated that 60% of
known and 75% of novel, ‘emerging’ human pathogens are zoonotic [9].
Diseases caused by zoonotic viruses are common, examples include tick
encephalitis, Dengue Fever, West Nile Virus (WNV), Zika (ZV), and
rabies (RBV) [9–11]. Zoonotic viruses are becoming increasingly common with the growth of human populations [11,12]. As the global
population swells, humans encroach into previously unsettled areas and
thus encounter animals carrying new viruses with ever-increasing frequency, especially in developing nations [7,10,13,14]. Furthermore,
rapid growth of industrial livestock farming inherently involves close
contact between dense populations of genetically homogenous animals
which allows viruses to rapidly reproduce and eventually spread to
humans [9,11,14].
Trends towards the emergence of new viruses due to population
growth, deforestation, and industrial agriculture are exacerbated by
climate change [15,16]. As average temperatures increase, arthropod
vectors carrying dozens of known viruses may expand their geographical
range and periods of seasonal activity. Of special prominence among
these are mosquitoes and ticks, which carry many serious viruses and
cause other non-viral illnesses as well [17–20]. Climate change can
magnify negative outcomes of viral diseases among especially vulnerable populations. Warming temperatures and pollution may apply
bodily homeostatic and immunological stress and decrease standards of
hygiene and medical care due to extreme weather events and geopolitical instability [21–23]. The worst outcomes of viral infection will
certainly be suffered by the Global South, where populations are
expanding rapidly and access to sanitary conditions and medical care
remains limited [23,24].
Amidst the devastation of COVID-19, as we consider the social dynamics of emerging diseases, there is an urgent need to reconsider the
strategies we use to confront widespread viral outbreaks. The sheer
scope of COVID-19's effect and lack of effectively coordinated response
indicates that there is a clear need for widely accessible AV therapies.
Such therapies may be derived from a variety of sources but should all be
grounded in a comprehensive understanding of viral structure/function
and infection progression.
Viruses are microscopic particles fundamentally consisting of a
genome surrounded by a protein capsid and/or a host membrane
derived lipid bilayer often referred to as an “envelope” [25]. Viruses are
abiotic obligate parasites, meaning that they depend on infecting living
organisms and ‘hijacking’ cellular machinery to reproduce [26,27].
During infection, viruses must enter the human body via epithelial tissues lining body surfaces or direct penetration into the bloodstream.
After invading the body, some viruses remain localized and replicate in
the tissues that first provided them entry. Others must circulate through
the lymph and blood to reach specific target tissues. In order to replicate,
viruses must invade particular cells and hijack cellular machinery to
produce copies of their genetic material and proteins. Viruses must carry
out these steps while evading or subverting the immune system [28,29].
Viruses utilize a vast array of highly specialized mechanisms to infect the
body and carry out their replication cycles [26]. These different mechanisms can be targeted by AV compounds at the various stages of viral
pathogenesis in order to prevent negative outcomes [30]. One holistic
strategy for developing AV therapies is to use an array of compounds
that act at different stages of infection in order to maximize drug efficacy
and avoid issues of bioavailability, harmful cytotoxic effects, and the
development of viral resistance through mutation that are common issues with some AV drugs [31–36].
Such bioactive compounds can be derived from natural or synthetic
sources [30,37]. Many naturally occurring AVs are optimal for use
because they are geographically widespread, abundant, easily refined,
and reliably produced from renewable sources [37,38]. One promising
source for AV compounds is algae. The term ‘algae’ refers to a polyphyletic grouping of ubiquitous mostly aquatic phototrophs distributed
throughout the world's bodies of salt and freshwater [39]. They are fast
growing and require low resource and energy inputs for cultivation.
Representing a phylogenetically diverse group of photosynthetic microand macroorganisms, algae are highly productive, renewable sources of
many bioactive compounds used in medicinal, cosmetic, commercial,
and food products as well as an intriguing source for the future generation of fuels [40–42]. Many studies reporting AV activities from algaederived compounds have been published in recent years.
Though the study of AV compounds from algae is still in its fledgling
stage, the base of literature nevertheless shows it to be a promising area
of inquiry. A Web of Science® database topic search for the string,
“algae antiviral” shows that prior to the year 2000, only 165 papers had
been published in this research area. 207 papers were published in the
years 2000–2010 and 741 from 2010-present (Fig. 1) [43]. This positive
trend indicates that algae are receiving increased attention as sources of
bioactive antiviral compounds and may, with further infrastructure
development and research into clinical applications, yield many lifesaving compounds.
In this review, we follow the steps of viral replication and discuss
algae-derived compounds that have demonstrated AV effects at each
stage. We begin with the invasion of viruses from the external environment into the human body, proceed to viral transport within the
body through the lymph and blood, and conclude by examining the
infection of target cells as well as immune response to viral infection
(Fig. 2). We discuss compounds derived from a broad diversity of
eukaryotic micro- and macroalgae as well as cyanobacteria (Fig. 3) that
inhibit or interfere with the life cycles of numerous types of virus
(Table 1). We demonstrate how due to their exceptional pharmaceutical
potential, algal-derived compounds deserve increased attention as potential sources of widely available AV compounds.
2. Viral pathogenesis
In order to replicate, a virus must hijack the machinery of specific
target cells in the human body [25]. However, the process by which a
virus infects the body and replicates itself is complex and varies
considerably between various groups of viruses. Viruses infect hosts
through a complicated series of steps and array of mechanisms. Generally speaking, a virion (virus particle) must first enter the human body
(Fig. 2A, B), which is well-protected against invasive foreign pathogens.
Many viruses enter the body by infecting layers of epithelial tissue which
line the body's borders. Others enter into the bloodstream through disruptions in the normally impenetrable layers of dermal tissue that cover
the vast majority of the body's surface [28,29].
Some viruses infect and replicate in the exterior layers of tissue that
first provided them entrance to the body. However, others require access
to non-epithelial tissues in order to replicate and thus necessitate
transport through the body via the lymph and blood, a process termed
viremia (Fig. 2B). In the lymph and blood, virions may encounter mobile
immune system phagocytes, namely macrophages and neutrophils that
are responsible for clearing the body of infectious foreign particles.
Virions that make their way into the blood are spread throughout the
body; however, certain types of viruses typically have highly specific
surface receptors that only bind certain target cells. Virions that come
into contact with their target cells will adhere to, penetrate their targets
(Fig. 2C) and release their genetic material for replication therein (using
some combination of viral and cellular machinery). Copies of viral
proteins and genetic material will then be packaged and released from
the cell through budding or apoptosis and will continue to infect more
target cells within the host or be released from the host into the environment to begin the cycle anew. Viral infections often cause a host
immune response (Fig. 2D), which may eliminate or reduce harmful
effects.
While they are complicated and highly variable between virus types,
viral pathogeneses provide many different avenues for intervention and
deterrence of infection. Algae-derived compounds may be administered
at many timepoints throughout the infection cycle to prevent harmful
effects by directly interfering with viral replication or boosting the
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Algal Research 57 (2021) 102331
Fig. 1. “Algae Antiviral” Publications 1956–2020. Annual publications containing the keywords “algae antiviral” since 1956, determined by Web of Science
Database topic search.
Fig. 2. Viral pathogenesis. In a generalized infection cycle, a virus must (A) enter the human body via a layer of epithelial tissue or (A′ ) directly into the bloodstream
via a dermal lesion, (B) be transported through the body via the lymph and blood, and (C) infect its target tissue, all while (D) evading or subverting immune response.
body's natural immune response. Some algae-derived compounds prevent infection from occurring by blocking common avenues into the
body. These represent proactive forms of treatment, preventing infection before it occurs.
2.1. Algal compounds prevent viral entry into the body
In order to cause infection, a virus must invade the human body. A
virus may access the body through different avenues (Fig. 4). While the
outer layer of dermal tissue is dry, dead, and impenetrable for viruses in
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4
Fig. 3. A broad diversity of algae produces antiviral compounds. Isolated compounds or crude extracts from genera depicted in Fig. 3 have demonstrated antiviral activity and are discussed in this review. These algae
represent marine and freshwater species distributed throughout the world.
Algal Research 57 (2021) 102331
D. Reynolds et al.
Algal Research 57 (2021) 102331
Table 1
Algae-derived compounds show inhibitory activity towards a broad diversity of viruses. Table 1 shows the families of viruses and associated diseases that have been
discussed in this review. Virus families are sorted by genome and envelope morphologies to indicate the structural diversity of viruses that are inhibited by algaederived compounds.
Genome type
DNA viruses
RNA viruses
Envelope
Genome strands
Virus and
associated
disease
Enveloped
Double-stranded
Herpesviridae
Non-enveloped
• Herpes simplex virus 1 & 2
(HSV-1 & 2)
• Equine herpesvirus (EHV)
• Feline herpesvirus (FHV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CTMV)
• Human
papillomavirus (HPV)
Papillomaviridae
Enveloped
Single-stranded
Paramyxoviridae
Non-enveloped
Double-stranded
Picornaviridae
• Newcastle disease virus (NDV)
• Respiratory syncytial virus (RSV)
• Parainfluenza virus (PIAV)
• Measles virus (MeV)
• Mumps virus (MuV)
Coronaviridae
• Enterovirus
(ENTV)
• Rhinovirus
(RHV)
• Hepatitis virus
(HV)
Single-stranded
Birnaviridae
• Infectious bursal
disease virus (IBDV)
Caliciviridae
• Norovirus (NoV)
• Severe acute respiratory syndrome
virus (SARS-CoV 1/2)
• Middle East respiratory syndrome
virus (MERS-CoV)
• Porcine epidemic diarrhea virus
(PEDV)
Rhabdoviridae
• Infectious hematopoietic necrosis
virus (IHNV)
Roniviridae
• Shrimp yellowhead virus (YHV)
Pneumoviridae
Hepadnaviridae
Adenoviridae
• Hepatitis B virus (HBV)
• Adenovirus
• Metapneumovirus (MPNV)
Orthomyxoviridae
• Influenza virus (IAV)
Retroviridae
• Human immunodeficiency virus
(HIV)
• Simian immunodeficiency virus (SIV)
• Avian leucosis virus (ALV)
• Avian myeloblastosis virus (AMV)
Flaviviridae
•
•
•
•
Zika virus (ZV)
Dengue virus (DENV)
Hepatitis C virus (HCV)
Japanese encephalitis virus (JEV)
its intact form, there are a number of living layers of epithelial tissue that
a virus can access through bodily orifices or exposed surfaces. These
primarily include the respiratory tract (coronaviruses (CoVs), influenza
viruses (IAVs), etc.), the alimentary tract (hepatitis (HV), cytomegaloviruses (CTMVs), etc.), the urogenital tract (human papilloma (HPV),
some herpes (HSV), human immunodeficiency viruses (HIV), etc.), and
more rarely, the conjunctiva (adenoviruses (ADVs), enteroviruses
(ENTVs), etc.) [28,44]. Epithelial tissues represent entry points that viruses can pass through on their way to infecting other bodily tissues.
Some viruses do not enter the body through epithelial tissues, but
instead by penetrating the skin through bites (rabies, Zika, Dengue Fever
viruses, etc.), scrapes (pox, some HSVs, etc.), or injections with
contaminated needles (Epstein-Barr (EBV), Ebola viruses (EV), etc.)
[28,44].
Therapeutic use of algae derived compounds is an example of a step
that can be taken to prevent viral entry into the body. Other common
preventative measures that lower the chances of internalizing environmental virions include wearing masks and washing hands. Indeed,
prevention measures, whether behavioral (i.e., washing hands, sterilizing needles) or technological (i.e., vaccines) are always preferable to
treatment as they avert any negative outcomes accompanying infection
and medical intervention. Here we discuss viruses that enter the body
through different avenues and corresponding preventative algae-
derived compounds (Table 2).
2.1.1. Respiratory epithelia
Respiratory viruses are incredibly widespread and the leading cause
of disease in humans around the world. They are responsible for roughly
one-fifth of all childhood mortality, especially in poor tropical regions
[66]. Respiratory viruses can spread rapidly through populations via
person-to-person contact. Typically, virions are inhaled from the air or
transmitted to the respiratory tract via direct contact (i.e., touching
fingers to the mouth or nose). Some compounds derived from algae are
able to protect against respiratory disease by preventing virion particles
from entering and infecting the respiratory tract epithelia (Table 2).
2.1.1.1. Carrageenan. Carrageenan is a sulfated polysaccharide derived
from various macroalgae in the phylum Rhodophyta including Gigartina,
Chondrus crispus, Eucheuma, and Hypnea [67,190]. In several recent
clinical trials, a carrageenan-based nasal spray demonstrated AV activity
against human common cold viruses by preventing viral attachment to
epithelial cells in the nasal cavity [45–47] (Table 2). Carrageenan bound
to viral glycoproteins and acted as a physical barrier preventing virions
from infecting their target cells. By limiting the number of viruses able to
access epithelial tissue, fewer viruses were able to replicate leading to a
reduction in viral titers and faster resolution of symptoms. Importantly,
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Algal Research 57 (2021) 102331
Fig. 4. Environmental virus particles commonly enter the body through a layer of epithelial tissue (conjunctiva, respiratory, alimentary, urogenital) or through
dermal lesion (bite, scrape, injection). Algae-derived compounds prevent viruses from infecting the body via each of these avenues.
Table 2
Algal compounds prevent the entrance of viruses into the body.
Mode of entry
Compound
Species classification
Species
Model
Virus
Reference
Respiratory
epithelia
Carrageenan
Rhodophyta
Not reported
Clinical trials,
murine
[45–48]
Fucoidan
Fucoidan
Phaeophyceae
Phaeophyceae
Kjellmaniella crassifolia
Undaria pinnatifida
Murine
Murine
Carrageenan
Rhodophyta
Not reported
Clinical trial
Rhesus macaque
Lectins
Assorted algae,
cyanobacteria
Rhodophyta
In vitro
In vitro; TZM-bl,
HeLa, Vero
MGDG
Diterpenes
Bromophenols
Protein
extract
PMG
Carrageenan
Chlorophyta
Phaeophyceae
Rhodophyta
Phaeophyceae
Various
Originally isolated from Griffithsia sp., produced
recombinantly in Nicotiana benthamiana
(Solanaceae)
Coccomyxa sp.
Canistrocarpus cervicornis
Symphyocladia latiuscula
Macrocystis pyrifera, Durvillaea antarctica
CoV
IAV
PIAV
MPNV
RSV
RHV
IAV-A
IAV-A
Avian IAV-A
HPV
HIV
HSV-2
Simian immunodeficiency
virus (SIV)
HIV
HPV
HIV
HSV-2, HPV
Murine
Murine
Murine
Murine
HSV-2
HSV-1
HSV-1
HSV-1, HSV-2
[60]
[65]
[62]
[63]
Phaeophyceae
Rhodophyceae
Not reported
Not reported
Murine
Feline
HPV
FHV-1
[64]
[65]
Alimentary
epithelia
Urogenital
epithelia
Dermal lesion
Conjunctiva
[49]
[58,59,61]
[53,54]
[55]
[56]
[57]
[58]
[59]
as a host-independent mechanism is unlikely to lead to adverse sideaffects. It was later shown that carrageenan can be paired with an
additional influenza-targeting drug to achieve a synergistic AV effect
and prevent the development of viral resistance [48]. The combination
therapy was able to prevent fatality from a lethal influenza strain in a
carrageenan acted as a non-specific physical barrier to several different
types of pathogen, including CoV, IAV, parainfluenza (PIAV), rhino
(RHV), metapneumonia (MPNV), and respiratory syncytial viruses
(RSV). Carrageenan did not itself pass through respiratory mucosa and
enter into the circulation. This mode of action is important to highlight,
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Algal Research 57 (2021) 102331
murine model. Because influenza virus infections are often accompanied
by other respiratory viruses, targeting with influenza-specific drugs
often fails to alleviate symptoms. Combination treatment with carrageenan can be an effective solution by acting as a non-specific barrier to
many different viruses that would otherwise cause harmful respiratory
disease making. Due to its ability to counter infection from a variety of
different viruses, carrageenan is an ideal broad-spectrum preventative
agent. Multiple carrageenan-based nasal sprays are currently marketed
in Europe and Canada [68,69]; additional research and investment
could provide a massive protective effect to vulnerable populations in
other countries around the world. A clinical trial evaluating the prophylactic effect of a carrageenan nasal spray against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently underway in
the United States [70] and similar efforts to develop an anti-SARS-CoV-2
carrageenan nasal spray are being made in the UK [71].
the result was not statistically significant, it is possible that a higher dose
would demonstrate a more robust discrepancy. It should be noted that
this study used a fucoidan sample with some impurities (7.2%) which
may have contained trace amounts of other bioactive compounds.
Furthermore, the fucoidan sample used exhibited a broad MW range
(20–1100 kDa) with a peak value of 72.1 kDa, and so it is possible that
some small amount of fucoidan uptake from the intestines occurred.
Thus, potentially confounding factors are the interaction between
fucoidan and virions in the bloodstream, immunomodulation, or inactivation at the lung epithelia.
Additional research by Synytsya et al. characterized a LMW (9 kDa)
fucoidan derived from Undaria pinnatifida called Mekabu fucoidan (MF)
[52]. This study showed that the oral administration of MF decreased
lung titers of two IAV subtypes by 70–85%. The authors proposed that
this reduction was due to both direct interaction between MF and virions
(preventing viral adsorption from the alimentary tract into circulation)
as well as immunomodulation by MF absorbed into the bloodstream.
Due to its direct inactivation of virions and activation of immune system
function, it is impossible to determine which mechanism predominated,
but it is likely that some AV activity in the alimentary tract decreased the
severity of infection.
Significantly, Synytsya et al. and Hayashi et al. both showed that the
oral administration of a LMW fucoidan resulted in a significant decrease
in lung IAV titer [50,52] (Table 2). Both studies also showed an
immunomodulatory effect from orally administered fucoidan. It is likely
that limited IAV replication can be attributed to both a direct inactivating effect from fucoidan molecules in the alimentary tract and its
immunostimulatory effects. Fucoidan may serve as an effective AV in the
alimentary tract and continue to exert further AV activity during later
stages of pathogenesis. In following sections, we will further discuss
fucoidan's AV activity, including its properties as an immunostimulant.
This research provides evidence that AV compounds may exert activity
by preventing viral absorption through intestinal epithelia.
2.1.1.2. Fucoidan. Fucoidan is a sulfated polysaccharide found in many
algae within the class Phaeophyceae. Using a murine model, Wang et al.
determined the intranasal application of fucoidan derived from Kjellmaniella crassifolia was able to protect against Influenza A virus (IAV)
pathology through a series of mechanisms [49] (Table 2). Fucoidan interacts with IAV surface enzyme neuraminidase (NA) in a hostindependent manner to form a stable, inert complex that prevents
viral entry into cells. Fucoidan may also interact with sialic acid residues
on the viral envelope to prevent activation of the epidermal growth
factor receptor (EGFR) pathway that would otherwise result in viral
endocytosis. Unlike the commercial drugs amantadine and Oseltamivir,
fucoidan did not give rise to resistant viral strains. The administration of
fucoidan in the nasal cavity prevented IAV infection in mouse models, as
lower titers of virus were recovered from the lungs after treatment.
Fucoidan's high molecular weight (MW) may prevent it from passing
through the respiratory mucosa or being absorbed by epithelial cells and
likely limits IAV virion interactions with cellular receptors.
2.1.3. Urogenital epithelia
The urogenital system is responsible for the formation and excretion
of urine as well as important reproductive functions. The urogenital
system is lined with epithelial cells and is susceptible to infection from
HIV, HPV, HV, and HSV [28,29]. Compounds derived from algae can be
topically applied to female urogenital epithelia to prevent invasion of
viruses, typically those associated with sexually transmitted diseases
(Table 2).
2.1.2. Alimentary epithelia
The alimentary tract consists of a series of organs involved with
consumption, digestion, and excretion. These primarily include the
mouth, pharynx, stomach, and intestines. The alimentary tract is lined
with layers of epithelial tissue for nutrient absorption and chemical
secretion. While protected with layers of mucus, bile, stomach acid, and
other deterrents, the alimentary tract is nonetheless vulnerable to
certain pathogens. Many viruses are ingested and infect the body via the
alimentary tract [28,29]. Some, like HSV, EBV, and CTMV invade the
cells of the mouth. Many others invade the intestinal tract, including
reoviruses, ADVs, Norwalk virus, ENTVs, HVs, and rotaviruses. Algaederived compounds administered in the alimentary tract via oral consumption have the ability to prevent viruses from infecting alimentary
epithelia (Table 2).
2.1.3.1. Carrageenan. In several clinical trials, topically applied carrageenan gels have shown effectiveness in preventing the spread of
sexually transmitted viruses. In a human trial with female volunteers,
the carrageenan-based, topically applied gel Carraguard was associated
with a 40% reduced likelihood of contracting HPV compared to control
subjects [53] (Table 2). The authors suggest that carrageenan acts as a
physical barrier, competing with and preventing HPV from binding to
epithelial cell receptors. Increased protection from HPV was associated
with adherence to consistent gel use. However, the study was nonetheless limited by inconsistencies in reporting and it is possible that an
even higher protection rate could be attained by improving behavioral
performance. Better adherence to the protocol by study participants
would improve the comparison's power as well.
In a later study, 40 women suffering from HPV infection used a
carrageenan-based, vaginally applied gel over the course of four months.
At the end of the trial, 60% of women using the carrageenan gel negatively tested for HPV infection, compared to 25% of control group participants [54]. HPV only replicates in the urogenital epithelia, and so by
preventing virions from entering epithelial cells, the carrageenan gel
was able to reduce and eventually eliminate HPV infection entirely for a
subset of study participants.
Another study showed that participants using the commercial
2.1.2.1. Fucoidan. Hayashi et al. found that a low molecular weight
(LMW) (9 kDa) orally administered fucoidan from the brown alga
Undaria pinnatifida was able to significantly decrease the IAV titer in
mice lungs, and that this benefit was augmented by combining treatment with the commercial pharmaceutical Oseltamivir (Table 2) [50].
Furthermore, treatment with oral fucoidan was able to entirely prevent
mortality. More recently, Richards et al. supported this result, determining that the oral administration of fucoidan from Undaria pinnatifida
was able to reduce symptoms and lung pathology after IAV infection
[51], potentially by preventing virions from interacting with alimentary
epithelia. In addition to infection and replication in the respiratory tract,
influenza viruses are known to replicate in the alimentary tract [72].
Due to its binding and inactivation of IAV, orally administered fucoidan
in the alimentary tract may prevent harmful interactions between the
virus and alimentary epithelia. Richards et al. showed that the administration of fucoidan led to a minimal decrease in viral titers [51]. While
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carrageenan-based gel Carraguard contracted fewer HIV infections than
controls, but the result was not statistically significant [55]. However,
this study was also severely limited by the poor adherence to regular gel
application before intercourse. It is thus possible that Carraguard may
yet be an effective clinical HIV solution. However, carrageenans have
been shown to only be effective against HIV at extremely high concentrations [73], and so it may be unlikely that carrageenans prove an
effective topically applied anti-HIV compound. Furthermore, this case
study shows how even effective solutions might be limited by real-world
application factors, an important consideration to keep in mind as the
various compounds in this study are discussed. Recent reports using
combination therapies showed that an intravaginal ring releasing
carrageenan as well as two other synthetic pharmaceuticals limited HIV,
HPV, and HSV infection in rhesus macaques [56,57] (Table 2).
acyclovir. Furthermore, the diterpene ointment showed promising activity against an acyclovir-resistant strain of HSV as well. The diterpene
ointment did not show harmful effects, alter hepatic or renal function,
nor reduce bodyweight. Diterpenes interfere with viral entry into target
cells by binding with viral glycoproteins [75], and so while virionditerpene complexes may have entered into the vasculature, the virions were unable to enter their target cells. Diterpenes do not form a
physical barrier in the same manner as some previously discussed
polysaccharide compounds. Topical application of diterpenes in this
manner may be an effective way to prevent against HSV infection. In
practice, one might apply a diterpene-containing ointment to a scrape,
sunburn, or otherwise damaged dermal tissue after injury to prevent
HSV infection.
2.1.4.2. Bromophenol. Bromophenols are small organic molecules containing at least one bromine atom covalently bonded to a phenolic ring.
Research performed by Park et al. determined that the oral administration of tribromophenolic compounds from the red alga Symphyocladia
latiuscula reduced the development of skin lesions in mice after HSV-1
infection (Table 2). This is remarkable, as mice were scratched and
infected with HSV-1 at the skin level but the oral administration of
bromophenol still exerted a protective effect. It seems probable that
bromophenols were taken up by the bloodstream and made their way to
the dermis where they exert their AV activity, limiting the number of
virions that entered the body. In addition to opposing HSV-1 infection of
dermal tissue, the topical application of bromophenol reduced yields of
virus in the brain, thus indicating that less virus was able to pass through
the dermis and enter the bloodstream. The efficacy of bromophenols
when applied either orally or topically is a promising indicator of
potentially robust AV activity [62].
2.1.3.2. Lectins. Lectins are non-immunoglobulin carbohydrate-binding proteins that can interact with glycans on viral envelopes to prevent
binding with target cells [58]. As topically applied microbicides, they
have great potential to limit viral infection. Research performed using
rhesus macaques found that the lectin cyanovirin (CV-N) from the cyanobacteria Nostoc ellipsosporum inhibited 63–85% of HIV infection [58]
(Table 2). Another demonstrated that griffithsin (GRFT), a lectin from
red algae (Rhodophyta), binds both HPV and HSV glycoproteins and
inhibits entry into their target cells [59]. Using a murine model, researchers showed that the combination of vaginally applied GRFT and
carrageenan protect against HPV and HSV infection. This is especially
significant with HSV, as HSV particles can be absorbed into the bloodstream after infecting urogenital epithelia and cause harmful pathologies to other tissue types.
2.1.3.3. Monogalactosyl diacylglycerol (MGDG). MGDG compounds are
fatty acids found in many organisms. Hayashi et al. found that the
vaginal administration of an MGDG fraction from the green (phylum
Chlorophyta) microalga Coccomyxa sp. exerted a prophylactic effect
against HSV-2 infection using a murine model [60] (Table 2). MGDG
decreased viral load in the urogenital cavity, reduced lesion formation,
and improved the survival rates of infected mice. MGDG was shown to
exert a protective effect by binding virion particles and degrading them.
The mechanism likely involves the MGDG compounds fusing with and
partially disrupting the lipid membrane of the viruses [74]. This
mechanism will be further discussed in Section 2.2.1 where we examine
virucidal compounds.
2.1.4.3. Proteins. Castillo et al. collected semi-refined cytosolic extracts
of two brown algae, M. pyrifera and D. antarctica [63] that were mostly
proteinous in nature but also included some additional small molecules
(Table 2). Two fractions were generated from the extract, one with
proteins >10 kDa in size and one with proteins <10 kDa. While the
larger protein fraction exerted stronger AV activity against HSV than the
smaller, both fractions together yielded the strongest effect in vitro.
Using a murine model, the investigators first inoculated skin lesions with
HSV and then applied a topical formulation of the protein extract to the
skin 24 h later. Due to the time course of experimental steps, virions
accumulated in the dorsal root ganglia, showing that the virus effectively infected the mice, but no viral accumulation was shown at the
skin. Thus, it is possible that the preemptive topical application of this
protein extract would prevent infection of the skin and other vulnerable
tissues targeted by HSV that require entrance to the body. This study
demonstrates an important point about therapeutic compounds derived
from natural sources: in the words of Sharaf et al., “Natural products
containing bioactive compounds are sometimes more effective in their
natural combination, rather than in a pure concentrated effective compound with identified composition” [76]. Unrefined extracts of natural
organisms may contain hundreds or thousands of compounds and it is
certainly possible that multiple of those may exert antiviral activity. Due
to the great diversity of compounds from natural sources, it is impossible
to identify every downstream effect of every compound within the
human body. An unrefined sample containing a multitude of compounds
may thus improve therapeutic efficacy by eliminating the effects of
harmful pathogens at various stages of the infection cycle, reducing the
likelihood for developing harmful mutations, and decreasing the cost of
treatment preparation [32,77].
2.1.4. Dermal lesions
Dermal tissue covers the vast majority of our body surfaces. Exposed
dermis is dead, keratinized tissue that is impenetrable to viruses in their
intact state. However, viruses are able to enter through openings in the
skin created by abrasion, laceration, injection, or bite. After penetrating
the skin, viruses may reproduce and cause damage locally or spread
through the blood to other regions of the body [28,44]. Many prevention
measures can eliminate the possibility of contracting certain viruses that
enter the body directly through disruptions of the skin, such as sterilizing needles, using mosquito repellant, etc. Some algae-derived compounds can prevent viral infection via the skin should its integrity be
damaged (Table 2). This protective effect can be achieved through
topical or oral administration.
2.1.4.1. Diterpenes. Diterpenes are small molecules composed of four
isoprene units and are found throughout nature. A diterpene-based
topical ointment from Canistrocarpus cervicornis, a brown alga (Phaeophyceae), was recently evaluated against the spread of HSV-1 via cutaneous lesion [61] (Table 2). In this investigation, mice were scratched,
inoculated with HSV-1, and then treated with diterpene ointment. The
diterpene ointment protected against lesion injury, paralysis, and death
as a result of infection in a manner similar to the synthetic drug
2.1.4.4. Polymannuroguluronate (PMG). PMG is a sulfated polysaccharide derived from seaweed in the class Phaeophyceae. Research
performed by Wang et al. found that an LMW (10 kDa) PMG had potent
anti-HPV effects in vitro and in vivo using a murine skin-infection model
8
D. Reynolds et al.
Algal Research 57 (2021) 102331
Fig. 5. Algae-derived compounds can limit viral spread through the vasculature. A., virucidal/virustatic compounds degrade virions or hold them inert and B.,
phagocyte-stimulating compounds boost phagocyte activity as they patrol the body looking for invading pathogens.
epidermis but is protected by constant secretions (tears) and wiping by
the eyelid. Compounds from algae may be able to protect against
infection of the conjunctiva.
[64] (Table 2). In this study, mice were scarified using an abrasive hand
tool and then inoculated with HPV in solution. When applied before or
concurrently with infection, PMG significantly limited infection. In vitro
analysis showed that PMG inhibits HPV through a series of mechanisms
which may prevent drug-resistant virus strains. Cytotoxicity assays also
revealed that PMG has an extremely high selectivity index (SI) and low
cytotoxicity in three different cell lines. PMG is thus a promising prophylactic treatment against HPV, the most common sexually transmitted
disease.
2.1.5.1. λ-Carrageenan. Stiles et al. found that λ-carrageenan from
seaweed in the phylum Rhodophyta limited feline herpesvirus-1 (FHV1) infection in vitro. When applied topically to the eyes of cats in vivo,
λ-carrageenan reduced the time period of viral shedding, when new
virions are produced and released into the environment, but did not alter
clinical signs of disease [65] (Table 2). Indeed, it seems that the application of λ-carrageenan in this experimental setup did not prevent
adsorption through the conjunctiva. λ-Carrageenan irritated some subjects after topical application. Research in this particular area is especially limited and more investigation is needed to elucidate any
potentially harmful effects or benefits of carrageenan application to the
conjunctiva.
2.1.5. Conjunctiva
The conjunctiva is the mucous membrane covering the eye and inside of the eyelids and is the route of entry into the body used by some
ADVs and ENTVs [28,29]. Recent evidence also demonstrated that the
SARS-CoV-2 virion can also infect the human body via the conjunctival
route [78]. The conjunctiva is more vulnerable to infection than the
Table 3
Algae-derived compounds exert virucidal and virustatic activities.
Activity
Compound
Species classification
Species
Model (cell line)
Virucidal
MC15
MGDG
Phaeophyceae
Chlorophyta
Eisenia bicyclis
Coccomyxa sp.
7-Keto stigmasterol
Phycobiliprotein
Chlorophyta
Cyanobacteria
Prasiola crispa
Spirulina platensis
In
In
In
In
In
Cyanovirin-N
GRFT
Cyanobacteria
Rhodophyta
Nostoc ellipsosporum
Griffithsia sp.
Lectins
Κ-Carrageenan
oligosaccharide
Fucoidan
Various
Rhodophyta
Various
Not reported
Phaeophyceae
Fucus evanescens
Ulvan
Xylomannan
p-KG03
AEX
Chlorophyta
Rhodophyta
Dinophyceae
Chlorophyta
GFP
PMG
Loliolide
Rhodophyta
Phaeophyceae
Phyllanthaceae (land plant)
Phaeophyceae, Rhodophyta,
Chlorophyta
Phaeophyceae
Rhodophyta
Chlorophyta
Phaeophyceae
Cyanobacteria
Phaeophyceae
Ulva pertusa
Scinaia hatei
Gyrodinium impudium
Coccomyxa
gloeobotrydiformis
Grateloupia filicina
Not reported
Phyllanthus urinaria
Various
Virustatic
Unknown
Polyphenol
Pheophorbide
Diterpenes
Arthrospira extract
Dolastane
Ecklonia arborea
Solieria filiformis
Dunaliella primolecta
Dictyota menstrualis
Arthrospira fusiformis
Canistrocarpus cervicornis
9
vitro (CHSE-214)
vitro (Vero)
vivo (Murine)
vitro (RK-13)
vitro (E. coli)
In vitro (PBL, MAC)
In vitro, (Vero, HEK-293, Huh7, MRC-5)
Various
In vitro (MDCK)
In
In
In
In
In
In
vitro (Vero, MT-4)
vivo (Murine)
vitro (DF-1)
vitro (Vero)
vitro (MDCK)
vitro (Vero)
In vitro (DF-1)
Virus
Reference
IHNV
HSV-1/2
[88]
[60]
EHV-1
MS-2
ΦX-174
HIV
MERS-CoV
[89]
[90]
HIV
IAV
[58]
[94]
HSV-1/2, HIV,
ECHO-1
ALV
HSV
IAV
IBDV
[95]
[91]
[92,93]
[96]
[97]
[98]
[99]
In vitro (Huh-7.5)
ALV
HPV
HCV
[100]
[64]
[101]
[102]
In vitro (Vero)
MeV
[103]
HSV-1
ZV
HSV-1
[104]
[105]
[76]
[106]
In
In
In
In
vitro (Vero)
vitro (Vero)
vitro (RC-37)
vitro (Vero)
D. Reynolds et al.
Algal Research 57 (2021) 102331
virustatic compounds. In order to do so, imaging or centrifugation to
isolate virion components is typically required to show virucidal activity. Virustatic action may be inferred by assays where an inactivated
virion is treated with a dissociation agent that would then lead to
reactivation and reveal the presence of a virustatic compound. Many
studies do not carry out the rigorous examinations required for mechanism elucidation; nevertheless, we report on direct inactivating compounds in this section, noting deficits in knowledge where appropriate.
As we discuss various algae-derived antiviral compounds, we present
information about their safety and pharmacokinetic profiles. Administration of drugs into the vasculature is dangerous as compounds are able
to diffuse throughout the body and interact with different cell types,
leading to unforeseeable and potentially negative outcomes. Where
applicable, we present information about effective or inhibitory concentrations of antiviral compounds (EC50, IC50), measures of drug potency that indicate the dose of a drug required to inhibit viral replication
or activity by 50%. We also report cytotoxicity indices (CT50), the concentration of a compound required to reduce cell viability in vitro by
50%. Wherever possible, we present the SI values of antiviral compounds which are calculated by dividing experimental EC50 or IC50 by
CT50 values. Higher SI values demonstrate drug potency without cytotoxicity and suggest specific interactions between drugs and their viral
targets. Drugs with a wide range of SI values are currently used in
various pharmaceutical applications. For example, the cardiac glycoside
digoxin has a therapeutic index of only 2–3 [85], while the opiate
anesthetic remifentanil has an SI >30,000 [86]. While drugs with high
SI values are safer, even drugs with low SI values can be utilized with
proper care.
An additional concern to keep in mind throughout our discussion of
AV compounds in the vasculature relates to drug diffusion and
bioavailability. Drugs administered intravenously are often inefficiently
transported through the circulation due to various properties including
size, polarity, and proclivity to form bonds with bond with other molecules [87]. Thus, it is important to keep these various factors in mind
when proposing antiviral candidates derived from algae to be administered in the vasculature. We discuss these factors where applicable.
2.1.6. Conclusion
For infection to take place, virions must bypass the body's external
defenses. By taking simple protective measures at this step, harmful and
costly infections can be prevented. Mask use, for example, has been
shown to prevent against the spread of SARS-CoV-2 as well as other
respiratory illnesses; wearing a mask to prevent the contraction or
transmission of such diseases is preferable to a potential hospital stay or
expensive antiviral therapies [79]. The best solution to a problem is
often proactive avoidance. In this section we have shown that compounds derived from algae including carrageenan, fucoidan, and lectins
among others have the potential to prevent infection from a variety of
harmful viruses at the initial stage of entry into the body (Table 2). In
subsequent sections we will demonstrate the antiviral activities of algal
compounds after infection has taken place.
2.2. Algal compounds inhibit viral passage through the body
Despite defense efforts, some virions are able to invade past both
natural and introduced exterior defenses and pass into the body. Some
viruses remain localized in external regions of the body, residing and
replicating in epithelial tissue [28,29]. Others are transported via the
vasculature to target tissues found throughout the body's organ systems.
These include togaviruses (TVs), ENTVs, orbiviruses (ORBVs), HSV,
EBV, CMV, and lentiviruses (LNTVs) among others [25]. Viremia is the
presence of viruses in the vasculature (lymph and/or bloodstream).
Recent results suggest that COVID-19 viremia is associated with critical
illness and more severe outcomes [80]. During their transport through
the body's vasculature, viruses may be inactivated by introduced or
endogenous interventions.
Non-native compounds that directly target virions may achieve a
delocalized protective effect when introduced to the vasculature (Fig. 5).
Generally speaking, compounds that target virions directly are virucidal
(degrading, damaging virions) or virustatic (binding virions and holding
them inert). Examples of both types of drug have been isolated from
algae (Table 3).
Endogenous defense is provided by the immune system. Compounds
from algae can boost the innate immune system during viral transport
through the vasculature, enhancing the activity of patrolling macrophages and neutrophils that are the body's first line of defense against
invading pathogens (Table 3), (Fig. 5).
2.2.1.1. MC15. Kamei et al. assayed extracts of 342 species of marine
algae against salmonid infectious hematopoietic virus (IHNV), a rhabdovirus related to human rabies virus (Table 3). The extract of the brown
alga Eisenia bicyclis showed particularly strong activity in vitro. The
active antiviral compound was purified and shown to be MC15, a
chlorophyll c2 derivative [88]. Time course experiments showed that
MC15 directly inactivated IHNV with a minimum inhibitory concentration of 0.8 μg/mL. Data suggests MC15 may damage lipid membrane
of enveloped viruses, as it showed inhibitory activity to other enveloped
viruses with both DNA and RNA genomes but did not affect nonenveloped viruses.
Chen & Roca demonstrated that a variety of chlorophyll molecules
and their derivatives from three species of Chlorophyta, Phaeophyte,
and Rhodophyta macroalgae were bioavailable upon metabolism using
an in vitro model [107]. This result suggests that MC15, a derivative of
chlorophyll C, would be absorbed into the vasculature following metabolism, but further research using an animal model is necessary to
confirm this result.
2.2.1. Virucidal and virustatic compounds from algae prevent vascular
spread
Virucidal compounds attack virion particles in their free state, disrupting their surface integrity or penetrating inside the capsid to destroy
their genome [81,82]. Virustatic compounds bind to the surface molecules of virions and hold them inert, preventing them from binding to
cell receptors and initiating infection. Certain compounds derived from
algae may exert virucidal or virustatic effects as they travel through the
body's vasculature (Table 3). These compounds may represent an ideal
form of treatment, as they do not invade the body's cells and may limit
the development of viral resistance [83]. They can be injected or
consumed orally, thus removing the need for administration by trained
medical professionals. Many such chemicals are found in algae. Hudson
et al. collected 16 species of Chlorophyte, Rhodophyte, and Phaeophyte
macroalgae off the coast of British Columbia and found (but did not
distinguish between) virucidal or virustatic activity from all of them
[84]. Clearly, there exists a great deal of potential in investigating the
virucidal/virustatic activity of algae-derived compounds. In this section,
we explore purified compounds from algae that demonstrate virucidal/
virustatic activity and note the difficulty in precisely elucidating antiviral mechanisms. While time-of-addition experiments can suggest that
a compound interferes with an early stage of the viral replication cycle,
such as binding or entry, pre-treating virions with compounds of interest
is generally necessary to show that a compound acts on virions and not
cells. Pre-treatment assays cannot distinguish between virucidal and
2.2.1.2. Monogalactosyl diacylglycerol (MGDG). Hayashi et al. demonstrated that an MGDG fraction from the green microalga Coccomyxa sp.
was actively antiviral against HSV-2 (Table 3) [60]. In vitro assays and
subsequent microscopy investigation showed that MGDG damaged viral
envelopes. The lipophilic MGDG molecule likely fuses with the viral
envelope, disrupting its integrity. MGDG EC50 was <13 μg/mL with a SI
of ~15. Topical administration of MGDG to the urogenital tract of female mice eliminated pathogenicity of HSV-2 infection, decreasing viral
yields and lesion formation, and increasing survival rates.
10
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Algal Research 57 (2021) 102331
MGDG may not be a viable candidate for oral administration as an
antiviral drug, as research indicates that structurally similar digalactosyl
diacylglycerides are degraded in the intestinal tract [108]. Diacylglycerols are important cell-signaling molecules [109], and while they
may be regularly cleared from the blood, might nevertheless exert
positive nutritional and antiviral effects when administered intravenously [110].
(Table 3) [58]. O'Keefe et al. demonstrated that cyanovirin-N, a lectin
extracted from marine cyanobacterium Nostoc ellipsosporum irreversibly
inactivates HIV virions in vitro. Cyanovirin-N is a 101 amino acid, 11 kDa
protein that displays high affinity for HIV glycoprotein 120 (gp120)
[91]. In vitro testing revealed that cyanovirin-N inhibited various HIV
laboratory strains and primary isolates with EC50 values <5 nM.
Crucially, cyanovirin-N binds viral gp120 in an irreversible manner and
prevents viral adhesion with target cells. Treatment with strong denaturing agents could not dissociate the cyanovirin-N-gp120 complex,
indicating that cyanovirin-N exerts a powerful virustatic effect on HIV
virions. Cyanovirin-N did not interact with cell receptors.
One recent study showed that the lectin GRFT from the red seaweed
Griffithsia sp. was able to bind the spike (S) protein of Middle East
Respiratory Syndrome Coronavirus (MERS-CoV) and prevent its interaction with target cells in vitro [92]. Other studies have shown how
GRFT demonstrates a broad spectrum of activity against other enveloped and non-enveloped viruses, and so while the predominant mechanism of this lectin is likely the direct inactivation of virions, there may
yet be other mechanisms at play as well [93].
In addition to their use as therapeutic compounds, lectins may even
improve the absorption and bioavailability of other drugs by facilitating
mucoadhesion, cytoadhesion, and cytoinvasion [116]. Zhang et al.
showed that insulin coupled to three different lectins showed high
bioavailability when administered orally [117]. Additional research
performed by Pooja et al. indicates that the anticancer drug PTX is more
bioavailable upon oral administration when conjugated to a lectin targeting ligand [118].
2.2.1.3. 7-Keto-stigmasterol. 7-Keto stigmasterol (Table 3), a ketosteroid isolated from the green alga Prasiola crispa, demonstrated inhibitory
activity against equine herpesvirus (EHV-1) [89]. Using in vitro assays
and time-of-addition experiments, 7-keto stigmasterol demonstrated a
direct virucidal effect on EHV-1 virions. Crucially, 7-keto stigmasterol
only interacted with the virion and not the cell or complex formed by the
virion attached to the cell. This is a promising finding for medicinal
application, as it suggests that 7-keto stigmasterol will not damage cell
surface integrity. 7-Keto stigmasterol demonstrated an EC50 value of 45
μM and SI from 20 to 47. Administering 100 μM of 7-keto stigmasterol
resulted in 100% inhibition of EHV-1. As a lipophilic steroid molecule,
the mechanism of virucidal action likely involves fusing with and disrupting the integrity of the viral membrane [89].
7-Keto stigmasterol belongs to the class of chemical compounds
known as phytosterols. Phytosterols may play a role in preventing heart
disease, although there are uncertainties regarding their safety [111].
Phytosterols are found in many plant oils along with long-chain fatty
acids that are an essential part of the human diet. When injected
parenterally as nutritional supplements, these long chain fatty acids are
accompanied by phytosterols. Phytosterols are not metabolized in the
human body and are excreted by the hepatobiliary system. Evidence
suggests that the overaccumulation of phytosterols in the blood may
lead to liver disease [112]. Thus, research into the use of 7-keto stigmasterol should be performed with caution.
2.2.1.6. Polyphenol. In a survey of polyphenol-rich extracts seaweed,
brown (Phaeophyte) macroalga Ecklonia arborea and red (Rhodophyta)
macroalga Solieria filiformis showed inhibitory activity against measles
virus (MeV) in vitro (Table 3) [103]. E. arborea and S. filiformis extracts
showed IC50 values against MeV of 3 and 0.5 μg/mL respectively. Timeof-addition assays indicate that the extract directly interacts with virions, preventing infection into target cells. Other sulfated polysaccharides, also extracted from seaweed, combined with the
polyphenol extract showed even stronger inhibition. No cytotoxicity was
detectable in the extracts, with E. arborea and S. filiformis showing SI
values of >3750 and >576.9 respectively, indicating strong potential for
drug development. This study did not differentiate between virucidal
and virustatic activity, however the authors suggest that the extract may
be used after infection to prevent viral spread throughout the body.
An additional study provides evidence that polyphenols exhibit a
direct inhibitory, virustatic effect on virion particles [119]. In this
investigation, administration of the polyphenols eckol, dieckol, and
phlorofucofuroeckol at concentrations ranging from 3.8 to 5.4 μM
completely blocked porcine epidemic diarrhea virus binding to target
cells in vitro. Time course experiments suggested that the binding of the
viral S-protein to prevent interaction with surface receptors mediated
the activity of these compounds.
Polyphenols are abundant in many commonly consumed plants.
They are a regular part of our diet and have recently garnered attention
as powerful antioxidant compounds. Polyphenols are typically
perceived as safe for consumption, although their bioavailabilities and
health effects differ widely among various polyphenol classes [120].
2.2.1.4. Loliolide. Loliolide is a lactone, produced in the degradation of
carotenoids, that has been isolated in many species of terrestrial plants
and algae and has demonstrated antimicrobial properties [113]. Chung
et al. found that loliolide extracted from the medicinal (non-algal) plant
Phyllanthus urinaria demonstrated AV activity against hepatitis C virus
(HCV) in vitro (Table 3) [101]. Loliolide demonstrated direct inactivating effect on virion particles, but a virucidal mechanism was not
observed. Loliolide may interact with the viral envelope or glycoproteins
in a virustatic manner, rendering virions unable to bind cell receptors or
fuse with the cell membrane. Loliolide inhibited HCV with an EC50
value of 3.1 μM and SI of 62.6. Interestingly, an unpurified fraction from
the Phyllanthus extraction demonstrated even stronger viral inactivation
than loliolide, indicating that there are other compounds contained in
the cytosol of Phyllanthus cells that may be promising avenues for
investigation. While the study reported on here did not use loliolide
derived from algae, because the same compound has been observed in
Phaeophyceae, Rhodophyta, and Chlorophyta algae it supports the use
of algae for producing AV compounds, especially as they generally
exhibit faster growth than terrestrial plants [114]. Loliolide is found
throughout many different organisms and has been incorporated into
many folk medicines around the world. It is used in diverse remedies as
an anti-bacterial, anti-inflammatory, anti-depressive, and anti-cancer
agent. Loliolide is thus likely a safe candidate for antiviral drug development [115].
2.2.1.7. Pheophorbide. Ohta et al. found that an extract of Dunaliella
primolecta, a green alga, had strong inhibitory activity against HSV-1 and
HSV-2 in vitro (Table 3). Purification of the extract revealed that the
active AV compounds had novel pheophorbide-like structures [104].
Pheophorbide is a product of chlorophyll degradation. In time-ofaddition assays, pheophorbide showed a strong direct inactivation or
denaturing of viral activity. Pheophorbide demonstrated an EC50 of 5
μg/mL, 100% inhibition at 10 μg/mL and no observable toxicity at 40
μg/mL. The study did not investigate a potential virucidal vs. virustatic
2.2.1.5. Lectins. Algal lectins are carbohydrate-binding agents that
recognize and bind specific residues on viral glycoproteins with a high
degree of specificity. Lectins do not covalently alter the viral glycoproteins or demonstrate virucidal properties, but rather, exert virustatic
activity by preventing their recognition of cell surface receptors [58].
Several lectins isolated from cyanobacteria and eukaryotic algae have
recently shown anti-HIV activity with high efficacy and low cytotoxicity
11
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Algal Research 57 (2021) 102331
effect, however due to its potency, low toxicity, and ubiquity of chlorophyll across the various groups of algae, pheophorbide might be a
promising candidate for drug development. Chen & Roca demonstrated
that products of chlorophyll breakdown from Chlorophytes, Rhodophytes, and Phaeophytes are bioavailable upon breakdown. Pheophorbide C was the most absorbable compound surveyed, suggesting
high potential for antiviral drug development [107].
hepatitis B virus, hepatitis C virus, and HIV. An extract containing
phycobiliproteins showed powerful virucidal action against both
phages, severely altering the morphological characteristic of their capsids and interfering with internalization into E. coli. Unlike some of the
other viruses we have previously examined, neither of the phages
studied in this experiment have lipid envelopes. Thus, it seems that the
phycobiliproteins are interacting with the protein capsid directly to
exert virucidal activity. This virucidal effect impaired replication and
lowered viral titer. Phycobiliproteins may thus hold some promise as
useful therapeutics against non-enveloped viruses such as rhinoviruses,
polioviruses, and noroviruses.
Mysliwa-Kurdziel & Solymosi reviewed phycobiliproteins used in
medicinal applications, and concluded that phycobiliproteins demonstrate bioavailability without any evidence of cytotoxicity when
administered via the oral route or injection [124]. Thus, phycobiliproteins are potentially safe, effective virucidal compounds. The Spirulina
cultures were collected from the Nile River in Egypt, supporting the
notion that potent antivirals can be derived from accessible sources in
diverse environments.
2.2.1.8. Diterpenes. Cirne-Santos et al. examined the AV activities of
extracts from the brown alga (Phaeophyceae) Dictyota menstrualis
against ZV in vitro and found that two extracts containing mainly
diterpenes had strong inhibitory potential (Table 3) [105]. An extract
fraction (FAc-2) rich in cyclic diterpenes exerted a virucidal pattern of
activity against ZV with an EC50 of 0.85 μg/mL and SI of 595.06. A 20
μg/mL treatment inhibited >90% of viral activity. While the investigators speculated that diterpenes in the FAc-2 extract might interfere with the viral capsid or the genome directly, the virucidal assay
carried out in this experiment did not implicate a specific mechanism.
However, the extract did not interfere with viral absorption, suggesting
that a virucidal or virustatic mechanism was at play.
Further research by the same group found anti-Chikungunya virus
(CHIKV) and anti-ZV activity from an extract of the brown alga
(Phaeophyceae) Canistrocarpus cervicornis in vitro and purified dolastane
(a subtype of diterpene) as the actively antiviral compound [106]. While
the crude extract was fairly potent against ZV and CHIKV with SI values
of 203 and 178 respectively, dolastane was even more potent with
experimental SI values of 1246 and 730 respectively. The EC50 values of
dolastane against both viruses were <3.5 μg/mL. Dolastane demonstrated a direct inactivating effect on virions, but it is uncertain whether
or not this mechanism was due to a virucidal or virustatic effect. However, due to dolastane's low molecular weight, inability to form many
hydrogen bonds, remarkable SI, and the relatively high potency of the
algal crude extract, this group of algae and dolastane-related compounds
deserve more scrutiny as potentially potent, accessible antiviral agents.
This is especially relevant in the Global South, the regions of the world
most affected by ZV and CHIKV.
The diterpenes discussed here are small molecules, with likely high
corresponding bioavailabilities. Research has shown that diterpenes
from other natural sources have high bioavailability and low toxicity
after oral and intravenous administration. Thus, diterpenes from algae
are promising candidates for antiviral drug development [121].
2.2.1.11. Caulerpin. Esteves et al. found that caulerpin, an alkaloid
derived from the green alga Caulerpa racemosa showed a strong direct
inhibitory pattern of activity against CHIKV in vitro [125] with an EC50
value of 3.1 μg/mL and an SI of 736.62 (Table 3). A concentration of 5
μg/mL caulerpin was able to exert a 100% inhibitory effect in preincubation virucidal assays. No investigation was made to differentiate
between the virucidal and virustatic mechanisms of caulerpin. However,
due to caulerpin's low MW, tendency to engage in minimal hydrogen
bonding, and high SI, this compound deserves further investigation as a
potentially potent AV compound. Furthermore, caulerpin has recently
been proposed as a novel inhibitor of the SARS-CoV-2 main protease
enzyme, suggesting that this compound may have multiple promising
modes of AV action [126].
2.2.1.12. Polysaccharides. Polysaccharides are long chains of sugar
molecules. They are remarkably diverse in their sugar constituents,
branching, and size. Polysaccharides are synthesized in cells for many
purposes including energy storage, structural stability, and cell
signaling. Antiviral polysaccharides frequently have virustatic mechanisms based on negatively charged molecules embedded within their
structure interacting with positively charged regions of the viral surface.
For brevity's sake and due to their similarities in mechanism, we
describe a few of the best characterized polysaccharides from three
major eukaryotic algal phyla showing virustatic activity and list others
(Table 3). We also describe some challenges associated with using
polysaccharides as antiviral drugs and potential solutions.
The sulfated polysaccharide carrageenan has virustatic and potentially virucidal properties [127]. Wang et al. examined a 2 kDa
κ-Carrageenan oligosaccharide and found that it exerted a direct inactivating effect on IAV in vitro [94]. The oligosaccharide had an IC50 value
of 32.1 μg/mL and an SI of 26.7. In this study, the carrageenan oligosaccharide had a direct inactivating effect on virions, likely mediated by
binding of anionic sulfate groups in the oligosaccharide to positively
charged regions of the viral surface. The finding that carrageenan was
unable to bind the cell surface supports the notion that it exerts a
virustatic effect. Interestingly, a different study suggested that carrageenan was able to modify the HSV glycoprotein gB, thus postulating
that carrageenan might exert some virucidal as well as virustatic activity
[128]. Carrageenan may have elicited a temporary, reversible change in
the virion structure and so uncertainty about its precise inactivating
mechanism remains. Nevertheless, the oligosaccharide form of carrageenan has potential as an AV drug.
Because carrageenan is generally high MW, it is perhaps not wellsuited to transport through the vasculature although some research indicates that carrageenan might be available for a short time in the
2.2.1.9. Arthrospira extract. Sharaf et al. examined the AV activity of
cold water, hot water, and phosphate buffer extracts of the cyanobacterium Arthrospira fusiformis and found direct inactivating effects on
HSV virions in vitro (Table 3) [76]. When pre-treated with these extracts,
viral replication was inhibited ~90%. No mechanism nor bioactive
compound was identified in this experiment; however, the authors
postulate that the buffer extract contained allophycocyanin as an active
component. This study used Arthrospira extracts from Egyptian and
American cyanobacteria and found similar activities in both strains.
Importantly, this demonstrates that even crudely extracted compounds
from geographically removed locations can exert powerful bioactivities
which bodes well for accessible drug production.
Additional studies have shown that phycocyanin, a similar phycobiliprotein from cyanobacteria, is bioavailable and non-toxic when
administered orally or via injection and may also have some powerful
anti-inflammatory effects [122,123]. Thus, allophycocyanin is a promising virucidal compound from Arthrospira that merits further research.
2.2.1.10. Phycobiliproteins. One experiment examined the AV activity
of a Spirulina (Arthrospira) platensis extract against two bacteriophages,
MS-2 and ΦX-174 in vitro (Table 3) [90]. MS-2, an ssRNA virus, is
commonly used as a model for human poliovirus, hepatitis A virus, and
enterovirus. ΦX-174 is a ssDNA virus commonly used as a model for
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vasculature after injection [129]. Indeed, this is one common issue
frequently encountered in the use of polysaccharides as intravenous
drugs [130]. However, the oligosaccharide is two orders of magnitude
smaller than typical carrageenan molecules, more easily absorbed, and
much more mobile traveling through the body. This study showed that
carrageenan oligosaccharide lacked cytotoxicity, but other concerns
about carrageenan cytotoxicity have been raised, especially in oligosaccharide form [67]. Thus, this question merits further investigation.
Carlucci et al. found that the administration of carrageenan was able to
select for a drug-resistant viral mutant, posing an additional concern
regarding carrageenan's use as a therapeutic intervention [128].
Another well-characterized polysaccharide showing diverse bioactivities is fucoidan, derived from brown (Phaeophyceae) macroalgae
such as kelp and sargassum. Krylova et al. examined the AV effect of two
fucoidans from Fucus evanescens for AV activity against HIV, HSV-1,
HSV-2, and enterovirus (ECHO-1) in vitro and in vivo [95]. One fucoidan was of high MW (~160 kDa), and one was enzymatically degraded
to a low MW (~50 kDa). Assays showed that both fucoidans directly
inactivated HSV-1/2 with mean SI values ~19. Both fucoidans showed
moderate direct inactivation of HIV with SI values ~8. Direct inactivation of ECHO-1 was minimal (SI ~3). Fucoidan's direct inactivating effects are due to a virustatic effect characterized by interactions between
anionic sulfate groups on the fucoidan polysaccharide and positively
charged regions of the viral surface. Later in vivo testing showed that
both fucoidans had a protective effect against intravaginal HSV-2
infection in a murine model when injected into the intraperitoneal
space, indicating that fucoidan is bioavailable upon injection. Protective
effects in vivo were also observed in a recent study which found that the
oral administration of fucoidan derived from Laminaria japonica protected against murine norovirus infection and increased survival rates in
a murine model [131]. In vitro testing showed that pretreatment of virions with fucoidan inhibited infection. An additional study provided
evidence that fucoidan interacts directly with the HSV virion. In time-ofaddition experiments, Sun et al. found that fucoidan did not have a
protective effect against HSV-2 infection when pretreated with the cell.
However, when added with the virus during infection, infection was
significantly inhibited [132]. In addition to inhibition of HSV, one
recent study also showed that fucoidan is able to bind the SARS-CoV-2 Sprotein, preventing the virion from binding to its target cells [133].
The sulfated polysaccharide Ulvan is derived from green (Chlorophyta) macroalgae. Sun et al. investigated the inhibitory potential of
ulvans with varying molecular weights on avian leukosis virus (ALV) in
vitro [96]. At 2 mg/mL, cell viability remained >95% indicating minimal cytotoxicity. In AV assays, ulvan showed an inhibitory effect at the
initial stage of viral adhesion but had no effect when pretreated with the
cell. Thus, ulvan is assumed to interact with virions directly in a virustatic manner. The results suggest that the negatively charged sulfate
groups likely bind to positively charged regions of surface glycoproteins.
In this study, ulvans with MWs of ~2–~160 kDa were surveyed for their
AV activity. A 4.3 kDa ulvan showed the greatest inhibitory potential.
Another study found that ulvan inhibited Newcastle Disease Virus
(NDV) spread between infected cells but did not interact with the virion
particle, displaying neither virucidal nor virustatic activity [134]. This
discrepancy in result is hardly surprising, considering the diversity in
viral envelope proteins and natural variability of polysaccharides between individual organisms. More research is needed to investigate the
potential for developing directly inactivating AV drugs from ulvan.
Carrageenan, fucoidan, and ulvan are three extensively characterized polysaccharides representing the three large taxa of red, brown, and
green macroalgae. Despite the immense diversity of algae, these three
polysaccharides largely operate through a similar mechanism: anionic
regions of the polysaccharides consisting primarily of sulfate and uronic
acids interact with viral glycoproteins to prevent glycoprotein-cell receptor complex formation. This interaction is virustatic, holding virions
inert and preventing infection. A similar mechanism has been suggested
across many other types of algae-derived polysaccharides, including
xylomannan [97], p-KG03 [98], AEX [99], GFP [100], and PMG [64].
Polysaccharides are promising compounds for drug development as
they display a wide range of bioactivities. However, using polysaccharides as intravenous drugs is challenging, due to their poor
transport through the vasculature, difficulty in diffusing across membranes, anticoagulant activity, and potential cytotoxicity [130]. One
potential solution is degradation into smaller oligosaccharides that
maintain similar bioactivities without the disadvantages of unwieldy
molecular size. Some studies show improved AV activity from low MW
polysaccharides produced through oxidative degradation [96,100].
However, concerns over the health effects of degraded polysaccharides
necessitate further investigation.
2.2.1.13. Conclusion. The compounds reported on in this section
(Table 3) directly inactivate virions by either binding them irreversibly,
preventing them from engaging with their target cells, or compromising
the virion's structural integrity. If introduced into the vasculature by
consumption or injection, these compounds may prevent virions from
interacting with their target cells. While some of the investigations
examined in this section distinguished between virucidal and virustatic
mechanisms, several did not. This necessitates more research, as the
compounds in this section represent some of the most auspicious
currently known antiviral compounds extracted from algae.
Many of the virucidal and virustatic compounds reported on in this
section were studied using in vitro models, which do not fully represent
living systems. It is likely that some of the bioactive compounds reported
on here would show harmful side effects or lose potency in vivo. However, the compounds described this section did not demonstrate harmful
side effects in vitro using a variety of cell lines. Furthermore, many of the
compounds preferentially bind virions and do not interact with cell
surfaces or receptors at all, suggesting that more research is needed on
the clinical applications of these compounds as antiviral drugs. Evidence
Table 4
Algae-derived compounds stimulate phagocyte activity.
Compound
Species
classification
Species
Activity
Model
Reference
Fucoidan
Phaeophyceae
Macrophage-activating
In vitro (murine macrophage)
[137]
Ulvan
Chlorophyta
Cladosiphon
okamuranus
Ulva rigida
Macrophage and neutrophil-activating
In vitro (Turbot phagocyte)
Laminaran
Alginate
Carrageenan
Phaeophyceae
Phaeophyceae
Rhodophyta
Rhodophyta
Laminaria hyperborea
Laminaria digitata
Chondrus ocellatus
Not reported
Eucheuma spinosa
Not reported
Porphyra yezoensis
Gracilaria verrucosa
Macrophage-activating
Neutrophil-activating
Macrophage-activating
Macrophage-destroying
Macrophage-inhibitory
Macrophage-activating mediates AV activity
Macrophage-activating and proliferationstimulating
Macrophage stimulation
In vitro (Salmo salar macrophages)
In vivo (Oncorhynchus mykiss)
In vivo (Cyprinus carpio)
In vivo (Murine)
In vitro (L929)
In vitro RAW264.7
In vitro & In vivo (murine
macrophages)
In vivo (murine macrophages)
[138]
[139]
[140]
[129]
[143]
[144]
[145]
[146]
[147,148]
[149]
Neoagarohexaose
Red algae extracts
Rhodophyta
Rhodophyta
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Algal Research 57 (2021) 102331
suggests that the compounds reported here could be administered orally
or via injection after infection and may prevent viruses from spreading
through the vasculature to reach and invade their target tissues. This is
preventative treatment, as inactivating virions before they reach their
targets avoids negative cytopathic effects entirely. Due to the diversity
of compounds, algae, and viruses (enveloped and non-enveloped) reported on in this section, directly inactivating antiviral drugs from algae
should be the subject of further investigation.
phagocyte activity through interaction with cell-surface receptors. One
recent study completed a chemical synthesis of Ulvan. The synthetic
Ulvan displayed immunomodulatory activities, augmenting the phagocytic activity of macrophages in vitro [152].
2.2.2.3. Laminaran. Laminaran is a polysaccharide storage product
derived from brown macroalgae (Phaeophyceae) and diatoms. Dalmo
et al. found that laminaran activates the salmonid (fish) non-specific
immune system, of which macrophages are a central component
(Table 4) [140]. Salmonid macrophages stimulated with laminaran in
vitro contained more vacuoles and granules, exhibited increased
phagocytotic and pinocytotic activity, generated elevated levels of superoxide, and showed higher activity of lysosomal enzymes when
compared to control cells. These are important components of the nonspecific response that phagocytes use to destroy invading pathogens,
including viruses. Laminaran was an effective immunomodulator of
salmonid macrophages. This finding is supported by further research
conducted by El-Boshy et al., 2010, which found that laminaran from the
brown (Phaeophyte) macroalga Laminaria japonica stimulates the
Oreochromis niloticus (tilapia) immune system against bacterial infection
[153]. Because it can be absorbed from the intestines into circulation,
laminaran has potential as an orally applied immune-boosting drug for
both fish (in aquaculture operations) and humans.
2.2.2. Phagocyte-stimulating algal compounds enhance innate immune
response
Viruses that invade past layers of epithelial tissue into the vasculature may also be inactivated by the patrolling cells that are components
of the body's innate immune response. In the vasculature, viruses
encounter a variety of mobile antimicrobial cells, including macrophages and neutrophils, which are the immune system's first line of
defense against invading pathogens [28,135]. Macrophages are large,
phagocytic cells encountered throughout the body's tissues and circulating in the blood. They are a crucial part of the primary immune
response after viral infection [28,29]. Neutrophils circulate in the blood
and are the first cells recruited to sites of infection or injury and are
responsible for antimicrobial defense via phagocytizing or caging novel
pathogens [136]. Algae-derived compounds can boost macrophage and
neutrophil activity, which may have an important protective role in
preventing viral infection (Table 4).
2.2.2.4. Alginate. Alginate is an acidic polysaccharide derived from the
cell walls of brown macroalgae (Phaeophyceae). Peddie et al. showed
that alginate from Laminaria digitata stimulates neutrophil migration
and phagocytosis using an in vivo piscine model (Table 4) [142]. In this
study, the injection of alginate caused a significant migration of leukocytes into the peritoneal cavity, with an increased proportion of neutrophils when compared to controls. Macrophage count decreased as a
result of alginate administration. The change in macrophage vs neutrophil concentrations is striking, as macrophages are typically more
concentrated in the piscine peritoneum. Alginate caused an elevated
expression of interleukins (IL) 1β and 8 as well as TNF-α. The elevated
expression of IL-8 may explain selective neutrophil activation, as IL-8 is
a chemoattractant cytokine showing a great deal of specificity for neutrophils. More research is required to elucidate specific interactions
between alginate and macrophages compared to neutrophils. In addition
to altered migratory patterns and gene expression, more leukocytes
exposed to alginate exhibited phagocytic activity. Alginate is thus a
promising immunostimulant with special neutrophil modulating properties. This is especially important in viral infection, as neutrophils are
the first cell recruited to sites of viral infection to clear pathogens and
initiate a proinflammatory response [136].
2.2.2.1. Fucoidan. In addition to its potential as a topically applied viral
blocking agent, the polysaccharide fucoidan may also have a positive
effect on the function of patrolling macrophage activity. Teruya et al.
determined that fucoidan from Laminaria angustata has an activating
effect on macrophages in vitro via interactions with the toll-like receptor
4 (TLR4), cluster of differentiation 14 (CD14), and scavenger receptor
class-A (SRA) receptors as well as the mitogen-activated protein kinase
(MAPK) signaling pathway (Table 4) [137]. Later, the same team
determined that fucoidan stimulated production of nitric oxide (NO),
tumor necrosis factor-α (TNF- α), and interleukin-6 (IL-6), molecules
produced by macrophages that are crucially important to immune
response [150]. They showed macrophage activation and demonstrate
that fucoidan is an immunostimulant. An additional study suggested
that phagocyte-stimulating agents might have an important role in defense against microbial infection. This investigation showed that in
addition to stimulating NO, TNF-α, and IL-6 production, fucoidan
elevated macrophage phagocytosis and lysosome enzyme activity [151].
Fucoidan was mitogenic (encouraging cell proliferation) in lymphocytes
and macrophages. These results were further supported by a recent
study showing that fucoidan induced macrophage activation via the
MAPK and NF-κB signaling pathways [135]. Significantly, this study
demonstrated the immunostimulatory capacity of an LMW fucoidan and
emphasized its potential for improved bioactivities and absorption.
2.2.2.5. Carrageenan. Shin et al. showed that the peritoneal injection of
κ-carrageenan caused the recruitment and migration of phagocytes from
the head kidney (analogous to the mammalian adrenal gland) to the
peritoneum using an in vivo carp model (Table 4) [143]. These migrated
phagocytes (especially macrophages) demonstrated increased levels of
phagocytosis and cleared a harmful bacterial infection resulting in
higher survival rates compared to controls. While the model was not
challenged with a viral infection, phagocytes are also important in
clearing viral pathogens, suggesting that κ-carrageenan can recruit the
immune system against viruses too.
Ogata et al. showed mixed results following the administration of
ι-carrageenan. Carrageenan primed leukocytes for production of TNF, an
important component of response to infection, but also destroyed macrophages [144]. An additional study demonstrated that ι-carrageenan is
inhibitory to murine macrophage activity [145]. These studies warn of
the potential mixed effects of immunomodulating agents. ι- and
κ-carrageenan differ slightly in structure [154] and this variation clearly
leads to a difference in functional properties. Both carrageenans
participate in cell signaling during important phases of immune
2.2.2.2. Ulvan. Ulvan is an acidic, sulfated polysaccharide produced in
the cell walls of many green macroalgae (e.g., Ulva spp., Chlorophyta).
Castro et al. showed that a crude extract from Ulva rigida stimulated
turbot (fish) macrophage and granulocyte activity as indicated by an
increase in reactive oxygen species (ROS) (Table 4). An increase in ROS
(primarily NO and H2O2) is a crucial component of AV response and is
important for recruiting phagocytes to help repel pathogens. This activity was largely attributable to polysaccharides [138]. The compound
from Ulva rigida stimulating this ‘respiratory burst’ was later identified
as an ulvan [139]. The desulfated ulvan did not show stimulatory activity, indicating the importance of the anionic sulfate groups in this cell
signaling pathway. Significantly, small and large polysaccharides both
stimulated the macrophage/granulocyte mixture, which is of considerable importance as large polysaccharides are not easily absorbed or
transported through the bloodstream. Ulvan probably stimulates
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Algal Research 57 (2021) 102331
response, but more research is needed to elucidate the specific mechanisms of each carrageenan's role. A thorough structure-function analysis
may elucidate certain types of carrageenan that augment beneficial effects of phagocytes without incurring a serious negative toll.
raising the possibility for easily administered medicinal food products.
2.2.2.8. Conclusion. As viruses travel through the lymph and blood,
they encounter mobile defensive cells of the immune system, namely the
phagocytes termed macrophages and neutrophils. These cells are a
crucial component of the body's innate immune response. In this section,
we have shown how algae-derived compounds boost the activities of
these cells by stimulating phagocytosis, inflammatory response via the
generation of ROS, and further immune system activation via interleukins, cytokines, and other signaling pathways.
The mobile phagocytic cells of our immune system are able to clear
the body of many viruses before they initiate large-scale infections.
Compounds from algae show the ability to boost the activity of these
cells (Table 4), exerting an important protective effect in the continual
effort to prevent against infection.
2.2.2.6. Neoagarohexaose (NA6). The oligosaccharide NA6 is derived
from agarose, a major component of red algae (Rhodophyta) cell walls.
Kim et al. examined the effect of NA6 administration on immune activation in vitro using a RAW264.7 cell line (Table 4) [146]. This study
determined that NA6 is an agonist for the TLR4 signaling pathway,
important in the production of proinflammatory cytokines (TNF, interleukins) and interferons (IFNs). This research demonstrated that NA6
administration primed macrophage anti-norovirus response, mediated
by IFN signaling. NA6 boosted induction of IFN-β and upregulated IFNregulatory factor-1, an IFN-stimulated gene. Oral administration of NA6
activated TLR4 signaling and thereby reduced norovirus loads [146].
2.2.3. Viral passage through the vasculature–conclusion
After invasion of the body, many viruses must be transported to
specific target tissues before they can replicate. Indeed, viruses do not
exert their most harmful effects until they reach their target tissues. By
intervening to counter viral infection during transport through the
lymph and blood, harmful cytopathic effects can be averted. In this
section, we have seen how compounds derived from algae can directly
inhibit and degrade virions, thus offering promising sources of drugs
than can be introduced to the vasculature. We have also seen compounds
that boost innate immune response, specifically augmenting the activities of macrophages and neutrophils, cells of the immune system that
travel throughout the body searching out and destroying harmful infectious particles. By these two mechanisms, algal-derived compounds
can protect against the worst effects of infection that come later when
viruses reach their target tissues. In the next section, we will examine
algae-derived compounds that can specifically interfere with stages of
the viral replication process at the cellular level.
2.2.2.7. Red algae extracts. Yoshizawa et al. examined the in vitro and in
vivo macrophage-boosting effect of sulfated polysaccharide fractions
isolated from the red (Rhodophyta) macroalga Porphyra yezoensis
(Table 4) [147]. Two fractions were isolated using water and acid solvents. Carrageenan may have been a principle component of both
fractions. The water-soluble fraction activated macrophages as indicated
by elevated levels of nitric oxide production. The acid-soluble fraction
did not increase nitrite production. The water-soluble fraction increased
production of IL-1 and TNF, while the acid-soluble fraction only stimulated production of TNF. In vivo effects of the fractions on phagocytic
activity were measured; the acid-soluble fraction stimulated phagocytosis more strongly than the water-soluble fraction. Increases in
phagocytosis stimulated by the acid-soluble fraction were due to
elevated activity of the phagocytes, as measurements of organ mass
revealed that the number of phagocytes remained the same. The watersoluble fraction, in contrast, increased the number of phagocytes but not
their relative activity. The differences in activities between the fractions
is attributable to variation in content: the water-soluble fraction had a
somewhat higher protein concentration, a lower proportion of 3,6-anhydrogalactose, and a higher molecular weight. Each fraction engaged
with signaling pathways in slightly different manners, however both
demonstrated activating effects of murine phagocytes that may have
immunopotentiating significance.
Yoshizawa et al. later expanded this investigation and found that
desulfation of the acid-soluble fraction reduced its ability to stimulate
macrophage activity in vitro [148]. Increased sulphation of the fraction
did not increase activity, indicating the importance of both the sulphation and specific physical conformation of the polysaccharides in their
engagement with the cell-signaling pathway. Specifically, researchers
identified the sulfate group at position C-6 as essential to macrophage
stimulation. The initial molecular weight of the acid-soluble polysaccharide was 400 kDa; digestion into smaller pieces decreased viscosity and increased macrophage stimulating activities. This is an
important observation, as bulky compounds often hamper drug delivery.
A partially digested oligosaccharide represents a more promising drug.
Yoshizawa et al. performed further research on an enzymatically
degraded water-soluble polysaccharide fraction of Gracilaria verrucosa,
another type of red (Rhodophyta) macroalga [149]. Researchers determined the principle component of the polysaccharide fraction was a
sulfated galactan, potentially carrageenan. Intraperitoneal injection or
oral administration of the polysaccharide fraction stimulated macrophage activity in vivo using a murine model. Intraperitoneal injection of
the polysaccharide elevated macrophage numbers and increased production of radical oxygen species (ROS). Chemiluminescence assays
showed that oral consumption of polysaccharide also stimulated
macrophage activity. This is a promising result, as it indicates that oral
consumption of the polysaccharide fraction from red macroalgae has an
immunostimulatory effect, thus suggesting adequate bioavailability and
2.3. Algal compounds inhibit the viral replication cycle
A virion that arrives at its target tissue will begin the replication
cycle. This involves invading target cells, hijacking cellular machinery,
and producing many hundreds or thousands of copies of viral genetic
material and accompanying proteins to the detriment of cellular function and survivability (Fig. 5). Often, the accumulation of virions within
the cell will cause lysis, thus releasing copies of the virus in the environment to carry out the same process all over again. Other viruses use
normal cellular processes to facilitate their release, allowing the cell to
remain alive longer. Some viruses cause chronic disease by incorporating their genetic material into the host genome and lying dormant for
years before reemerging to continue the infection cycle [27].
The replication process is tremendously variable between different
types of virus. This variability is concerning from a healthcare standpoint, as it makes the development of broad-spectrum antiviral drugs
difficult. However, the specificity and complexity of a virus' interactions
with its given target cell allows for directed interventions that operate at
different timepoints during the replication cycle. In this section, we
explore the cycle of a generalized viral infection at the cellular level and
examine the steps at which algae-derived compounds might be deployed
to combat viral infection. It is important to note that each antiviral
compound presented in this section faces the same challenges with
bioavailability and cytotoxicity as those presented in Section 2.2. Many
of the studies discussed here are performed in vitro, which may highlight
promising compounds for antiviral drug discovery, but does not offer a
comprehensive picture of drug administration, transport, absorption,
and delivery. Every compound has a characteristic pharmacokinetic
profile which means that drug development must proceed deliberately
and meticulously to guarantee drug efficacy and safety.
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Table 5
Algae-derived compounds prevent viral adhesion to target cells.
Compound
Species
classification
Species
Virus
Model
Reference
Palmitic acid
Galactan
Phaeophyceae
Rhodophyta
Calcium spirulan
Cyanobacteria
HIV-1
HSV-1/2
HSV-1/2
HSV-1, CTMV, MeV, MuV, IAV,
HIV-1
HSV-1
In vitro (MΦs & PBL)
In vitro (Vero)
In vitro (Vero)
In vitro (Vero, MDCK, HeLa, HEL, MT-4)
In vitro (Vero)
[155]
[156]
[157]
[158]
[159]
Allophycocyanin
Cyanobacteria
Enterovirus-71 (EV71)
Cyanobacteria
Cyanobacteria
Chlorophyta
In vitro (Vero, human
rhabdomyosarcoma)
In vitro (Vero)
In vitro (Vero)
In vitro (Vero)
[160]
Arthrospira extract
Nostoflan
Chlorella polysaccharide
extract
Sargassum fusiforme
Gracilaria corticata
Schizymenia binderi
Spirulina (Arthrospira)
platensis
Spirulina (Arthrospira)
platensis
Spirulina (Arthrospira)
platensis
Arthrospira platensis
Nostoc flagelliforme
Chlorella vulgaris
HSV-1
HSV-1
HSV-1
[161]
[162]
[163]
Strikingly, the monounsaturated palmitoleic acid, which is otherwise
identical to palmitic acid, had a powerful virucidal effect on bacteriophage Φ6 particles. Differences in hydrocarbon structure thus lead to
alternate function in compound-virion-host cell receptor interactions.
Palmitic acid also demonstrated anti-HSV activity [165]. One additional study extracted lipophilic fractions from the brown (Phaeophyceae) macroalga Sargassum vulgare and found that the primary bioactive
compound was a sulfoquinovosyldiacylglycerol (SQDG) [166]. The
SQDG in question was esterified primarily by palmitic acid and displayed potent anti-HSV-1 activity. The authors speculate that this activity may have been in part due to the bioactivities of the abundant
palmitic acid, which may compete with HSV particles to bind cellular
receptors.
2.3.1. Adhesion
A virion that comes into contact with its target cell must bind to the
cell surface before it is able to be internalized. Surface molecules on viral
capsids or envelopes bind to receptors on cell surfaces. Viruses have
evolved the ability to bind many human host cell receptors; however,
the receptors have other functions besides the binding of virions. For
example, the ligand of human RHV, VP1,3, binds the important intracellular adhesion molecule ICAM-1 (the cellular receptor evolved to
carry out cell signaling and important to inflammatory response). Some
viruses bind multiple receptors on their target cells [28]. Many algaederived compounds have demonstrated the ability to prevent viral
adhesion, thus blocking infection. Preventing adhesion is another ideal
point of interference in the viral replication cycle, as treatments preventing adhesion are non-invasive and thus potentially carry reduced
risk of interference in important cellular processes. This ‘prevention’ of
infection at the cellular level is akin to masking the cell. However, it is
important to note that introducing exogenous compounds that that
interact with cells may have many unforeseeable, potentially harmful
downstream effects.
In Section 2.2.1, we discussed many algae-derived compounds that
prevent viral binding by directly interacting with the virion independent
of the target tissue, either rendering the virion inert or degrading it. In
this section, we discuss compounds that prevent viral adhesion in
context of a target cell. Some compounds discussed here compete with
the virus for binding cellular receptors and some bind only the complexed virion and surface receptors but not either one independently.
Some may interfere with conformational changes of proteins or block
signaling pathways essential for viral adhesion (Table 5).
2.3.1.2. Galactan. Mazumder et al. isolated a sulfated galactan polysaccharide from the red (Rhodophyta) macroalga Gracilaria corticata
that demonstrated anti-HSV-1/2 activity in vitro (Table 5) [156]. A
virucidal assay demonstrated that the isolated galactan did not exert any
direct inactivating effect on virions at IC50 concentration, suggesting
that galactan inhibited HSV at an alternative point in the replication
cycle. However, time of addition experiments indicated that galactan
only showed AV activity during the initial adsorption stage of infection,
suggesting that it interfered with the interaction of cell receptors and
viral glycoproteins in a cell-dependent manner. These results are supported by another study that showed how a galactan isolated from the
red (Rhodophyta) macroalgae Schizymenia binderi demonstrated antiHSV-1/2 activity with extremely high selectivity indices (>1000) in
vitro [157]. The authors postulated that the sulfated galactan interferes
with interaction between HSV particles and cellular heparan sulfate
residues that serve as the primary receptor for viral binding. This result
further suggests that galactan interferes with the viral adsorption
mechanism without directly inactivating the virus itself.
2.3.1.1. Palmitic acid. Lee et al. isolated a saturated fatty acid known as
palmitic acid from the brown (Phaeophyte) macroalgae Sargassum fusiforme and determined that it exerted anti-HIV-1 activity in vitro against
CXCR4 and CCR5-tropic viruses (Table 5) [155]. Treatment with 100 μM
of palmitic acid reduced infection in both CXCR4 and CCR5 viruses by
up to 70%. Treatment with 22 μM of palmitic acid inhibited CXCR4
infection in peripheral blood lymphocytes by 95% and treatment with
100 μM of palmitic acid inhibited CCR5 infection in primary macrophages by 90%, indicating effective broad-spectrum activity. Fluorescence spectroscopy demonstrated that Palmitic acid prevented HIV
binding to T-cells by competing for the binding of the CD4 receptor
necessary for viral attachment. This study found that the use of an
identical molecule with a slightly shorter hydrocarbon chain was unable
to prevent HIV infection, emphasizing the specificity of palmitic acidCD4 receptor binding.
Supporting the proposed anti-adhesion mechanism demonstrated
here by palmitic acid, an earlier study found that palmitic acid inhibits
bacteriophage Φ6 replication but does not inactivate virions [164].
Palmitic acid only prevented infection at the early stage of infection,
suggesting a similar virion-independent inhibition of attachment.
2.3.1.3. Calcium spirulan. Calcium spirulan, a sulfated polysaccharide
from the cyanobacterium Spirulina (Arthrospira) platensis, has demonstrated AV activity against an array of viruses (Table 5) [158,159]. In a
study conducted by Hayashi et al., calcium spirulan showed AV activity
in vitro against HSV, CTMV, MeV, mumps (MuV), IAV, and HIV with SI
values of 8587, 578, 371, 274, 574, and 1261 respectively [158]. No
activity against polio or coxsackievirus was observed, indicating selectivity for enveloped viruses. Time-of-addition assays showed AV activity
at multiple points during infection, but preincubation with cells showed
the most potent AV effect. Calcium spirulan most actively prevented
viral adsorption, indicating that calcium spirulan likely interacts with
the cell to prevent viral attachment. The broad spectrum of activity,
reported longer half-life in murine blood compared to other sulfated
polysaccharides [167], as well as the fact that these assays were performed across a variety of cell lines highlight calcium spirulan as a
promising medicinal agent.
16
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Algal Research 57 (2021) 102331
Table 6
Algae-derived compounds prevent viral entry into target cells.
Compound
Species
classification
Species
Virus
Activity
Model
Reference
SPMG
Phaeophyceae
Not reported
Block interaction between CD4 and gp120
Phaeophyceae
[49]
PML
Chlorophyta
In vitro (Vero)
[170]
MWS
Chlorophyta
Kjellmaniella
crassifolia
Monostroma
latissimum
Monostroma nitidum
Surface plasmon resonance with rgp120
and sCD4
In vitro (MDCK)
[168,169]
KW
HIV1
IAV
In vitro (Vero)
[171]
EV71
EV71
Inactivate EGFR pathway-mediated virion
internalization
Inactivate EGFR pathway-mediated virion
internalization
Decrease expression of EGFR protein
2.3.1.4. Allophycocyanin. Shih et al. found that allophycocyanin, a 104
kDa pigment protein extracted from Arthrospira platensis effectively
prevents enterovirus 71 (EV71) infection in vitro using Vero and human
rhabdomyosarcoma cells [160]. When added to cell cultures prior to
viral inoculation, allophycocyanin reduced infection with an SI of ~27
as observed in a plaque reduction assay. This effect was reduced when
allophycocyanin was added post-infection. This result suggests that
allophycocyanin prevents viral adhesion to target cells; however, more
research is required to elucidate whether allophycocyanin interacts with
host cell receptors, viral glycoproteins, or virus-cell complexes.
and is invaginated by the cell membrane [28,29]. Secondly, a virion
(enveloped) adhered to the cell membrane will fuse its own surface
envelope with that of the cell membrane, releasing its contents inside of
the cell [27]. Certain algal-derived compounds inhibit this step by
interfering with vital protein machinery (Table 6). In considering antientry mechanisms, one should bear in mind how it is difficult to
experimentally determine between anti-entry and anti-adhesion modes
of drug action. Time-course assays are typically not sensitive enough to
distinguish between the two and more advanced experiments are typically required.
2.3.1.5. Arthrospira extracts. Rechter et al. assayed the antiviral activity
of semi-refined Arthrospira platensis extracts in vitro [161]. These extracts
consisted of varying amounts of polysaccharide and protein, potentially
including previously-discussed compounds such as calcium spirulan and
allophycocyanin. The extracts showed anti-HSV and CTMV activity that
was most pronounced when preincubated with the cells (Table 5). Timeof-addition assays indicate that the compounds were active during the
adsorption and penetration stages of viral infection. Virucidal assays
showed that preincubation of compounds with virions significantly
decreased infection when compared to preincubation of compounds
with cells. This suggests that the compounds in the extracts bound cell
surface receptors to inhibit viral adhesion and entry.
2.3.2.1. Sulfated polymannuroguluronate (SPMG). The low weight
sulfated polysaccharide SPMG is extracted from brown (Phaeophyceae)
macroalgae [172]. SPMG has displayed anti-HIV effects in vitro which
can be attributed to a unique anti-entry mechanism. In order to infect Tcells, HIV virions depend on interactions between the CD4 cell receptor
and viral glycoprotein 120 (gp120). The binding of CD4 and gp120
result in the exposure of a previously hidden domain of gp120, the V3
loop. When exposed, the V3 loop binds another chemokine receptor
colocalized with CD4 and exposes viral glycoprotein 41 (gp41), which
facilitates cell-virus fusion [173]. SPMG is able to interfere with this
mechanism, as elucidated by one x-ray crystallography study (Table 6)
[169]. SPMG, it seems, binds to both the V3 loop and the CD4 receptor to
form a trimolecular complex. Additionally, SPMG may bind to gp120
residues other than the V3 loop in a cell-independent manner. SPMG is
potentially able to operate through a few mechanisms, binding to either
gp120, CD4, or both to inhibit gp120 attachment and viral entry. A
further study characterized SPMG's interaction with lymphocytes and
determined that SPMG binds positively charged epitopes on the CD4 cell
receptor in a polyanion mediated, highly specific, multivalent manner
[168]. Thus, SPMG may represent a novel, promising way to treat HIV
infection by interfering with the viral entry mechanism. SPMG entered
into clinical trials in China, passing Phase I and entering into Phase II
[172].
2.3.1.6. Nostoflan. Kanekiyo et al. assayed AV activity of an acidic
polysaccharide, nostoflan, isolated from the cyanobacterium Nostoc
flagelliforme against HSV-1 in vitro (Table 5) [162]. Nostoflan was found
to interfere with the initial binding stage of infection, but not with independent virions or the subsequent penetration of virions into the cell.
Notably, no protective effect was observed when target cells were preincubated with Nostoflan, indicating that nostoflan does not bind to cells
or virions independently. This presents the possibility that nostoflan
may only bind a virion-surface receptor complex. Furthermore, nostoflan's adhesion mechanism may depend on conformational changes in
either or both viral surface glycoprotein receptors and CD4 receptors.
2.3.2.2. Epidermal growth factor receptor (EGFR) pathway inhibitors. The
EGFR pathway is activated in many human tissues and is crucial to
epithelial and epidermis cell differentiation and growth [174]. Activation of this pathway also facilitates the entry of some types of virus into
cells. Eierhoff et al. showed that EGFR promoted the entry of IAV into
the cell [175]. Some algae-derived compounds inhibit viral infection via
blocking the EGFR pathway. Interfering with the EGFR pathway is also
potentially dangerous due to its importance in normal cell function. This
must be considered when developing antiviral drugs that interfere with
the EGFR pathway.
In a study conducted by Wang et al., a fucoidan from the brown
(Phaeophyceae) macroalgae Kjellmaniella crassifolia inactivated the
EGFR pathway in vitro to prevent the internalization of IAV (Table 6)
[49]. In another study, the sulfated rhamnan polysaccharide PML from
the green (Chlorophyta) macroalgae Monostroma latissimum reduced
EV71 infection in vitro and increase mouse survival in vivo. While PML
did have some direct inactivating effect on a viral capsid protein, it also
targeted the EGFR pathway to prevent internalization of EV71 particles
[170,171]. It is important to note that some compounds from algae
2.3.1.7. Chlorella polysaccharide extract. Santoyo et al. examined the in
vitro anti-HSV-1 activities of acetone, ethanol, and water extracts of the
green microalga Chlorella vulgaris (Table 5) [163]. Water and ethanol
extracts were able to inhibit 70% of infection at concentrations of 75 μg/
mL when used to pretreat cells. After promising initial testing of crude
extracts, further concentrated polysaccharide fractions inhibited HSV-1
infection to an even greater degree. Pretreatment of cells with semirefined polysaccharide fractions inhibited 90% of HSV-1 infection. It
is possible that some AV activity can be attributed to the presence of
phytol, but the majority of activity is likely due to polysaccharides. Due
to their high SI value (49.04), polysaccharides from Chlorella are
potentially valuable anti-adhesive AV drugs.
2.3.2. Entry
Viruses enter target cells through one of two mechanisms. First, a
virus may enter the cell through endocytosis. This mechanism is typical
of enveloped and non-enveloped viruses. In this mechanism, the virioncell receptor complex interacts with the cell surface molecule clathrin
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Algal Research 57 (2021) 102331
Table 7
Algae-derived compounds prevent viral uncoating.
Compound
Classification source
Species
Virus
Activity
Model
Reference
Fucoidan
Carrageenan
Phaeophyceae
Rhodophyta
Cladosiphon okamuranus
Not reported
DENV-2
DENV-2
Interferes with EGP
Prevent virion release from endosomes
In vitro (BHK-21)
In vitro (Vero, HepG2)
[177]
[178]
activate the EGFR pathway as well [176]. While some viruses may use
the EGFR to facilitate entry into target cells, it is important to remember
that EGFR signaling is required for proper functioning of epidermal
tissue, and so many unforeseen consequences may result from the
administration of even (seemingly) benign naturally-derived compounds that interfere with this pathway.
Fucoidan interfered with the action of this glycoprotein, potently
inhibiting infection.
Talarico et al. showed that carrageenan prevents DENV uncoating
using an elegant set of experiments in vitro (Table 7) [178]. DENV virions that penetrated into the cell via endocytosis were treated with
λ-carrageenan which prevented uncoating within the cell. Injecting
DENV RNA facilitated infection as usual, indicating that no replication
or transcription step was affected by carrageenan. While carrageenan
had previously demonstrated anti-DENV activity [179], this was the first
demonstration of a specific anti-uncoating mechanism. Due to their wide
range of molecular weights and corresponding differences in diffusion
properties, it is possible that some LMW carrageenans are able to enter
into cells and prevent uncoating of other types of virus as well. Carrageenan can enter into cells to inhibit later steps of the viral replication
cycle [180], but more research and specific experimental designs akin to
those of Talarico et al. are needed to reveal any anti-uncoating activities.
Indeed, many algae-derived compounds display AV activity postadhesion and entry but operate by undefined mechanisms. Such compounds include aplysiatoxins from cyanobacteria [181], which inhibit
CHIKV activity post-infection in vitro as determined by time-of-addition
experiments. However, uncertainty remains concerning the specific
2.3.3. Uncoating
Instructions from the viral genome are essential for directing further
steps of the replication process. While some transcription and translation steps may take place inside the viral capsid, oftentimes the viral
genetic material must be released into the cytosol or cell nucleus. Many
RNA viruses replicate in the cytosol and thus require the release of their
genetic material outside the nucleus, whereas some DNA viruses require
release inside the nucleus [27]. Some algae-derived compounds block
viral infection at the uncoating stage (Table 7).
Fucoidan exerts anti-DENV activity in vitro mediated by interference
with the viral internalization/uncoating step (Table 7) [177]. The DENV
mechanism of entry and uncoating depends on the EGP glycoprotein,
which mediates attachment, endocytosis, and fusion between the viral
membrane and endosome to release genetic material into the cytosol.
Table 8
Algae-derived compounds inhibit the viral replication cycle.
Compound
Species
classification
Species
Virus
Activity
Model
Reference
Dolastatin 3
Cyanobacteria
Lyngbya majuscula
HIV-1
Anti-HIV-1 integrase
[182]
Macroalgae extracts
Ecklonia cava, Ishige okamurae, Sargassum
confusum
Sargassum hemiphyllum, Sargassum ringgoldianum
Various
HIV-1
HIV-1
HIV-1
Anti-HIV-1 integrase and RT
Anti-HIV-1 integrase
Anti-HIV-1 RT
8,8′ -Bieckol
Phaeophyceae
Phaeophyceae
Chlorophyta (1
species)
Phaeophyceae (8
species)
Rhodophyta (6
species)
Phaeophyceae
N/A (enzyme
assay)
N/A (enzyme
assay)
N/A (enzyme
assay)
N/A (enzyme
assay)
Ecklonia cava
HIV-1
Anti-HIV-1 RT, protease
[184]
DEHC
Phaeophyceae
Ishige okamurae
HIV-1
Anti-HIV-1 integrase and RT
Diterpenes
Phaeophyceae
Dictyota menstrualis
HIV-1
Fucan, fucoidan,
alginic acid
Phaeophyceae
HIV-1
Alginate, ‘911’
Not reported
Dictyota mertensii
Lobophora variegata
Spatoglossum schroederi
Fucus vesiculosus
Not reported
Anti-HIV-1 DNA synthesis,
likely mediated by anti-RT
activity
Anti-HIV-1 RT
N/A (enzyme
assay)
N/A (enzyme
assay)
In vitro (PM-1
from Hut78)
HIV-1
HBV
λ-Carrageenan
Rhodophyta
Schizymenia pacifica
SQDG
Rhodophyta
Peyssonol A
Cyanobacterial
extracts
[183]
[183]
[183]
[185]
[186]
N/A (enzyme
assay)
[187]
Anti-HIV-1 RT
Anti-HBV DNA polymerase
In vitro (MT4)
HepG2215
HIV
Anti-HIV RT
Gigartina tenella
HIV-1
Anti-HIV RT
Rhodophyta
Peyssonnelia sp.
HIV-1
Anti-HIV-1/2 RT
Cyanobacteria
AMV
HIV-1
Anti-RT
In vitro (MT-4),
enzyme assays
N/A (enzyme
assay)
N/A (enzyme
assay)
N/A (enzyme
assay)
[188]
Surveyed
[173,183]
[191]
Inhibit RNA expression
In vitro (MDCK)
[94]
Inhibit RNA/protein
expression
RNAi
In vitro (Vero)
[119]
In vivo (Penaeus
vannamei)
[195]
κ-Carrageenan
oligosaccharide
Phlorotannins
Rhodophyta
Nostoc, Phormidium, Oscillatoria, Chroococcus,
Schizothrix, Aphanocapsa, Synechococcus,
Aphanothece, Xenococcus
Not reported
Phaeophyceae
Ecklonia cava
IAV
(H1N1)
PEDV
dsRNA
Chlorophyta
Chlamydomonas reinhardtii
YHV
18
[192]
[193]
[194]
D. Reynolds et al.
Algal Research 57 (2021) 102331
replication step that aplysiatoxins inhibit CHIKV. More emphasis will
need to be placed on AV research from algae to specifically elucidate the
mechanisms of potentially life-saving drugs. In the next sections we
examine algae-derived compounds that show AV activity at viral life
cycle steps that take place inside the cell and involve replication of viral
genetic material or proteins.
phaeophytes inhibited HIV-integrase. Three species, Ecklonia cava, Ishige
okamurae, and Sargassum confusum inhibited HIV-RT and integrase,
highlighting these species as particularly worthy of investigation going
forward. This study did not determine which specific compounds were
bioactive components of the methanolic extracts but eliminated potential contribution from polysaccharides by further fractionation with
ethylacetate. Follow-up research from the same team found that phlorotannins extracted from E. cava exerted strong anti-HIV-RT activity in
vitro [184]. Four compounds were isolated: eckol, 8,8′ -bieckol, 8,4′′′ dieckol, and phlorofucofuroeckol A. 8,8′ -bieckol showed particularly
strong anti-HIV-RT activity and displayed uncompetitive inhibition with
a Ki of 0.23 μM. Additional investigation also showed that the phlorotannin diphlorethohydroxycarmalol (DEHC) from I. okamurae showed
anti-HIV-RT and integrase activity with IC50 values of 9.1 μM and 25.2
μM respectively [185]. Taken together, these studies seem to indicate
that that the bioactive compounds from the initial methanolic extract
study were likely phlorotannins. These studies demonstrated that a wide
range of algae species across different phyla inhibited HIV-replication
and serve as a promising foundation for future AV research.
In a different study, diterpenes from the brown (Phaeophyceae)
macroalga Dictyota menstrualis showed anti-HIV activity in vitro using a
mechanism involving the inhibition of DNA integration or synthesis
(Table 8) [186]. In this study, diterpenes prevented double-stranded
DNA synthesis. Inhibition of HIV production as a whole occurred on
the same order of magnitude as observed in a specific anti-RT assay,
suggesting anti-RT activity as a primary mechanism for AV activity.
Diterpenes have been shown elsewhere in vitro and in molecular docking
analyses to inhibit HIV-RT [197].
Due to the global prevalence of HIV, potential anti-RT mediated
treatments have been researched extensively, including many algaederived compounds. Compounds from algae that have shown antiHIV-RT activity include fucan [187], alginate [188,189], λ-carrageenan [191], and sulfoquinovosyldiacylglycerol [192]. The latter also
inhibited eukaryotic polymerases and displayed some cytotoxicity. This
demonstrates an important point regarding anti-HIV research. RT enzymes are a type of DNA polymerase, and inhibitors of RT may inhibit
cellular DNA polymerase as well. It is vital to carefully develop anti-RT
drugs that do not interfere with essential cellular functions.
One interesting HIV-RT inhibitor that illustrates this point is peyssonol A, a sesquiterpene hydroquinone derived from the red macroalga
Peyssonelia sp. [198]. Loya et al. showed that peyssonols A and B inhibit
anti-HIV-RT activity and while peyssonol B showed moderate inhibitory
activity against eukaryotic DNA polymerases, peyssonol A showed very
little activity against DNA polymerases even at extremely high concentrations (Table 8) [193]. This result is promising, as it suggests a high
degree of selectivity for only HIV DNA synthesis and would likely not
result in adverse effects against human cells. In recent follow-up
research, analogues of peyssonol A were synthesized [199]. These analogues all exhibited anti-RT activity and varying degrees of cytotoxicity
in vitro. The authors suggest several compounds that deserve special
consideration going forward.
Exploring cyanobacterial compounds is another especially exciting
area of research that may reveal many RT inhibitors. Lau et al. surveyed
over 900 cyanobacterial extracts for their ability to inhibit AMV and HIV
RT enzymes (Table 8) [194]. 18 aqueous extracts showed promising
activity and further refining generated fractions that had RT specificity
and did not interfere with cellular genetic material.
Hepatitis B virus (HBV), a double-stranded DNA (dsDNA) virus that
causes chronic liver disease, uses a viral DNA polymerase to replicate its
genome [30,200]. One polysaccharide derived from a brown seaweed,
referred to as 911, inhibited HBV replication in vitro with an IC50 value
of 17.3 mg/mL and SI of 3.37 (Table 8) [201]. The researchers
concluded that the activity of 911 was due to inhibition of the HBV
polymerase enzyme. While this is a unique bioactivity that may have
significant therapeutic value, the low SI value of this compound is
concerning, and more research is needed to either identify similar, more
2.3.4. Replication
Replication refers to the process by which viral genetic material is
ultimately used to produce copies of itself and the protein components
essential to viral structure and function. Viral information is encoded in
either RNA or DNA which varies in its orientation (positive or negative
sense), segmentation (number of overall pieces of RNA or DNA), and
number of strands (single or double). DNA viruses must undergo transcription and translation to produce their proteins, akin to living organisms. Positive-sense single stranded RNA virus genomes are
essentially mRNA and can be directly translated into proteins once the
genome enters the cytoplasm after infection. However, replication of
positive-sense single stranded RNA genomes requires a virus-encoded
RNA dependent RNA polymerase as host cells do not have this type of
enzyme. In contrast, negative-sense RNA viruses must first synthesize
the complementary strand of mRNA before viral proteins can be translated. Retroviruses, including HIV, utilize a special enzyme to synthesize
double-stranded DNA from an RNA template prior to integration into the
host genome [28].
The replication of genetic material and proteins is highly variable
between virus types. This complicates antiviral drug development but
provides many possible avenues for intervention. Many algae-derived
compounds are able to interfere with specific steps of viral replication,
with a range of specificity (Table 8). In this section, we outline the AV
bioactivities of algae-derived compounds against the steps of viral
genome replication.
2.3.4.1. DNA synthesis. DNA replication is an important part of some
viral life cycles. DNA viruses replicate using either cellular or viral
polymerases. Polyoma, parvo-, circo-, and anelloviruses require cellular
DNA polymerase to replicate while ADVs, poxviruses, and HSVs use
their own DNA polymerase. Many viruses integrate their genetic material into host cell chromosomes as part of their life cycle [28]. This viral
DNA can immediately produce proteins important for the completion of
the viral life cycle or lay dormant, potentially for years, before actively
producing viral machinery. Some viruses, most famously retroviruses
like HIV, rely on a reverse transcriptase (RT) enzyme that uses an RNA
template to synthesize a double-stranded DNA ‘provirus’ that can be
incorporated into the host genome. Inhibiting this enzyme is a potentially effective way to prevent infection and many algae-derived compounds have demonstrated the ability to do so. Many algae-derived
compounds derive AV activity from inhibition of DNA integration or
synthesis processes (Table 8).
Preventing integration of viral DNA via inhibition of integrase enzymes may be one effective way to prevent chronic infection. The cyclic
peptide dolastatin 3 was isolated from a marine cyanobacterium, Lyngbya majuscula, and shown to demonstrate anti-HIV integrase activity in
vitro, though with a relatively poor IC50 value of 5 mM (Table 8) [182].
Cyanobacterial peptides may be promising AV agents, but little research
has been performed into this area. Dolastatins from other sources have
shown cytotoxicity [196]; further research is needed to clarify the potential benefits and drawbacks from dolastatin 3 and similar unique
compounds derived from cyanobacteria.
In a 2002 study, Ahn et al. screened the methanolic extracts of 47
Korean macroalgae species for anti-HIV-RT and anti-HIV-integrase activity [183]. These enzymes are not indigenous to human host cells and
thus are appealing potential targets for AV drugs. 15 of the 47 species
across Chlorophyta, Rhodophyta, and phaeophyte groups inhibited HIVRT (Table 8). Among all the macroalgae tested, only five of the
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Algal Research 57 (2021) 102331
Table 9
Algae-derived compounds inhibit viral processing after replication.
Compound
Species
classification
Species
Virus
Activity
Model
Reference
8,8′ -Bieckol 8,4′′ ′ Dieckol
Dieckol
Phaeophyceae
Ecklonia cava
HIV-1
Anti-HIV-1 protease
N/A (enzyme assay)
[184]
Phaeophyceae
Ecklonia cava
Anti-3CL protease
N/A (enzyme assay)
[204]
Ichthyopeptins A/B
Cyanobacteria
Microcystis ichthyoblabe
SARSCoV
IAV
In vitro (MDCK)
[205]
Brassicales
Rhodophyta
Isatis indigotica (land plant)
Halosaccion ramentaceum, Rhodomela confervoides,
Porphyra sp., Polyides rotunda
Caulerpa racemosa, Chondria armata, Sargassum
platycarpum
Protease inhibition
(proposed)
Anti-3CL protease
In vitro (Vero)
[206]
[207]
Anti-SARS-CoV-2-3CL
protease
Molecular docking
analysis
[126]
β-Sitosterol
Caulerpin
Chlorophyta
Rhodophyta
Phaeophyceae
potent compounds or chemically refine this compound for improved
antiviral properties.
SARSCoV
SARSCoV-2
enzymes that are not involved in normal cell functions.
After translation, viral proteins that are translated as a polyprotein or
a series of connected viral proteins must be cleaved into individual
functional proteins by cellular or virus encoded proteases. The viral
proteins can then mediate a range of functions including packaging of
viral proteins and genetic material into assembled units to be released
from the cell as mature virions. Many processing steps occur independently of cellular machinery and can thus be targeted by AV compounds
from algae (Table 9) [27].
HIV protease activity is crucial for the development of mature
structural and enzymatic proteins. The HIV protease is essential to the
viral life cycle but plays no part in human cellular function and makes an
excellent antiviral target. In a study conducted by Ahn et al., phlorotannins isolated from the brown macroalga E. cava showed moderate
inhibitory activity towards HIV protease in vitro (Table 9) [184]. These
phlorotannins showed more potent anti-RT activity than anti-protease
activity, suggesting the potential for the development of a multimechanism drug.
Recently, the steroid β-sitosterol extracted the land plant Isatis indigotica from was shown to inhibit the SARS-CoV-1 3C-like protease in
vitro with an IC50 of 1210 μM (Table 9) [206]. В-sitosterol is also found
in red (Rhodophyta) macroalgae [207], and should be researched along
with similar compounds as a potential anti-SARS-CoV-2 drug. The SARSCoV-1 main (3CL) protease is essential for proteolytic processing [208]
and has received attention as a potential target for AV therapy.
Abdelrheem et al. screened 10 natural compounds against the SARSCoV-2-3CL protease and determined that the alkaloid caulerpin
derived from green (Chlorophyta) algae in the genus Caulerpa showed
the most potent inhibitory activity [126]. Caulerpin satisfies Lipinski's
Rule of Five and ADMET properties. These are guidelines for drug
development relating to pharmacokinetic properties including molecular size, proclivity to engage in bonding, and bioavailability [209,210].
Compounds that satisfy these guidelines, such as caulerpin, are generally
perceived as promising candidates for further development. Further
investigation determined that caulerpin could be synthetically modified
to increase protease binding affinity [211].
One other study found that eight phlorotannins isolated from the
brown macroalga E. cava inhibited the SARS-CoV-1 3CL protease in vitro
[204]. In this study, dieckol showed especially potent inhibitory activity
(IC50 = 3.3 μM, SI >2.9). This experimental result was further examined
by molecular docking analysis, which demonstrated competitive-type
inhibition with a high association rate and strong hydrogen bonding.
The use of phlorotannins as protease inhibitors may be substantiated by
an extensive investigation carried out by Cannell et al. which surveyed
the protease inhibitory activity of extracts derived from 500 species of
eukaryotic algae and 80 species of cyanobacteria [212]. This investigation determined that 39 of the species in question showed protease
activity against at least one of seven enzymes surveyed (Table 9).
Significantly, almost all of the protease inhibitory activity came from
methanolic extracts where polyphenolic/phlorotannin compounds are
2.3.4.2. RNA synthesis. RNA synthesis is essential in the life cycle of all
viruses as a common step in protein synthesis and for the replication of
RNA virus genetic material. In order to replicate, RNA viruses must
synthesize copies of their genetic material, often using an RNAdependent RNA polymerase (RDRP) enzyme. The RDRP enzyme uses
an RNA strand to synthesize mRNA or RNA to serve as the viral genome
in future generations. Multiple kinds of RDRP exist depending on the
virus and the orientation (positive or negative sense) of its genome.
Some compounds derived from algae inhibit RNA synthesis, an important step in some way during the life cycle of all viruses (Table 8).
Wang et al. showed that a LMW carrageenan oligosaccharide entered
into cells and inhibited IAV mRNA expression in vitro (Table 8) [94].
Time of addition experiments indicated that carrageenan was active
after viral internalization and before viral release. Carrageenan did not
inhibit entry of virions into the cell, but displayed similar properties to
the commercial pharmaceutical Ribavirin, a known mRNA synthesis
inhibitor of IAV. Carrageenan thus seems to be an mRNA synthesis inhibitor in its LMW form. This is promising, as we have already illustrated
that carrageenan inhibits multiple viral replication steps. The multiple
modes of operation hold promise for effective AV activity with reduced
likelihood of developing viral resistance.
Many polyphenolic compounds inhibit RNA synthesis. In a study
conducted by Ryu et al., two phlorotannins derived from the brown
(Phaeophyceae) macroalga E. cava inhibited PEDV RNA and protein
synthesis in vitro (Table 8) [119]. One recent study performed molecular
docking on plant-derived polyphenols as inhibitors of the SARS-CoV-2
RDRP enzyme [202]. Four compounds showed exceptional promise
and were highlighted. While none of the compounds in this study were
derived from algae, similar compounds are found throughout the
different groups of algae. More research into algae-derived compounds
would certainly yield inhibitors of viral RNA synthesis.
2.3.4.3. RNA interference. RNA interference (RNAi) requires the introduction of a specific dsRNA molecule to target, bind and tag viral mRNA
for degradation so that viral proteins cannot be produced [203]. Algae
have shown promise as biofactories for specific dsRNAs and have
already been used to prevent YHV outbreak in aquaculture operations
(Table 8) [183]. RNAi has been used effectively against coronaviruses
and has been proposed as a potential therapy against SARS-CoV-2 [203].
2.3.5. Processing
After viral transcription has occurred, mRNAs are translated into
proteins. Viruses lack ribosomes, and so rely on host cell ribosomal
machinery to complete this step. Due to the high likelihood of interfering with cellular protein synthesis, using ribosome inhibitors as AV
compounds carries potentially catastrophic consequences. Thus, safe AV
compounds inhibiting viral protein synthesis interfere with specific viral
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Algal Research 57 (2021) 102331
Table 10
Algae-derived compounds inhibit viral release.
Compound
Species
classification
Species
Virus
Activity
Model
Reference
KW Fucoidan
Phaeophyceae
IAV
Anti-neuraminidase
Phaeophyceae
Anti-neuraminidase
Naviculan
Palmitic acid
Cyanovirin-N
Bacillariophyta
Phaeophyceae
Cyanobacteria
Microvirin
Griffithsin
Ulvan
Cyanobacteria
Rhodophyta
Chlorophyta
IAV (H1N1,
H3N2, H9N2)
HIV-1
HIV-1
HIV-1
HIV-1
HIV-1
HIV-1
NDV
In vitro (MDCK)
In vivo (murine)
In vitro (MDCK)
[49]
Phlorotannins
Kjellmaniella
crassifolia
Ecklonia cava
Allophycocyanin
Cyanobacteria
Durvillaea antarctica
polysaccharide
Phaeophyceae
Navicula directa
Sargassum fusiforme
Nostoc ellipsosporum
Unknown
Microcystis aeruginosa
Griffithsia sp.
Ulva clathrata
Spirulina (Arthrospira)
platensis
Durvillaea antarctica
EV71
Anti-syncytia formation
Anti-syncytia formation
Anti-syncytia formation
Anti-syncytia formation
Anti-syncytia formation
Anti-syncytia formation
Block F-protein cleavage, antisyncytium formation
Anti-apoptosis
EV71
Anti-apoptosis
concentrated. None of the protease enzymes in this study were specifically derived from viruses, however, the broad range of anti-protease
activities observed across different species of algae suggests that many
algae may produce anti-protease compounds that effectively inhibit
viral replication.
Zainuddin et al. isolated a fraction from the cyanobacterium Microcystis ichthyoblabe containing two ichthyopeptins, cyclic depsipeptides
that inhibited IAV with an IC50 of 12.5 μg/mL (Table 9) [205]. The
authors speculate that their antiviral activity is due to protease inhibitory activity. Cyanobacteria have been shown to produce many
protease-inhibitory compounds [213,214], further research may show
useful applications in combatting viral disease.
In
In
In
In
In
In
In
vitro (CD4-expressing HeLa)
vitro (MΦs, PBL)
vitro (CD4+ HeLa)
vitro (TZM-bl)
vitro (CD4+ T-cells)
vitro (CEM)
vitro (Vero)
In vitro (Vero, human
rhabdomyosarcoma)
In vitro (Vero)
[216]
[217]
[155]
[91]
[218]
[219]
[220]
[134]
[160]
[221]
2.3.6.1. Cell-cell transmission. As an alternative to being released from
cells, some viruses induce the cells they have infected to fuse with other
neighboring cells and form syncytia, multinucleate aggregations of cells
with one continuous cytoplasm that facilitate the spread of a virus with
greater efficiency through a given tissue [25,28]. HIV is an example of a
virus that causes syncytia to form, directing the fusion of CD4-expressing
cells [226]. HSV and Newcastle Disease Virus (NDV) are also spread
between cells by syncytia formation. Algae-derived compounds can
prevent syncytia formation (Table 10).
2.3.6.2. Naviculan. Lee et al. extracted the sulfated polysaccharide
naviculan from the diatom Navicula directa and determined that it prevented syncytium formation using an HIV fusion assay in vitro (Table 10)
[217]. Naviculan also interferes with infection at the adsorption/penetration stage as determined by time-of-addition experiment. Thus,
naviculan is a potential multi-mechanism anti-HIV agent that could be
useful in managing chronic infection. In this study, naviculan also
showed antiviral activity against HSV-1, HSV-2, and IAV with SI values
of 270, 310, and 32 respectively. Thus, naviculan has potential to be
developed into broad spectrum antiviral drug.
2.3.6. Budding/release
Virions may be released from the cell by budding through the
membrane or by cell lysis. Enveloped viruses are primarily released by
budding [215]. These viruses may acquire their envelopes from the
nuclear membrane, the Golgi membrane, endoplasmic reticulum, or cell
membranes. Budding is mediated by interactions between viral surface
molecules and proteins at the cell surface. Algae-derived compounds
have shown the ability to prevent viruses from being released into the
environment and continuing the infection process by interfering with
this machinery (Table 10).
Neuraminidase is an influenza surface enzyme that facilitates the
release of virions from infected cells after replication [222]. Wang et al.
showed that fucoidan from the brown macroalga (Phaeophyceae)
Kjellmaniella crassifolia inhibits neuraminidase in vitro (Table 10).
Furthermore, fucoidan limited IAV infection, increased survival, and
decreased viral titers in a murine model in vivo [49]. Phlorotannins
isolated from Ecklonia cava also demonstrated neuraminidase-inhibitory
activity [216]. Five phlorotannins showed inhibitory activity against
neuraminidase, with three of the five compounds showing potent antineuraminidase activity (IC50 < 50 μM) against enzymes derived from
three different influenza strains (H1N1, H3N2, H9N2) (Table 10). Inhibition of this enzyme was noncompetitive and acted synergistically
with the commercial pharmaceutical neuraminidase inhibitor oseltamivir. Because neuraminidase is also involved in the entry of influenza
virions into the cell [223], anti-neuraminidase drugs may be an effective
way to manage and limit the spread of influenza infection.
HIV assembly and budding depends on the modification of the Gag
protein with myristic acid [224], a saturated fatty acid found in some
red algae [225]. Lindwasser et al. found that the addition of mono- or
polyunsaturated myristic acid derivatives to infected cells interfered
with HIV assembly and release (Table 10) [224]. Synthetically modified
myristic acids extracted from algae could represent a promising way to
reduce the spread of HIV in infected patients.
2.3.6.3. Palmitic acid. In another study, palmitic acid from the brown
alga (Phaeophyceae) Sargassum fusiforme inhibited HIV infection in vitro
by preventing the interaction of the viral glycoprotein gp120 and
cellular CD4 receptor (Table 10) [155]. Palmitic acid prevented the
interaction of gp120 and CD4 by competing with gp120 for CD4 binding, thus reducing syncytia formation by up to 70%. In Section 2.3.1.1,
we described how palmitic acid exerts a powerful anti-adhesive affect to
inhibit HIV replication. Due to its multi-mechanism anti-HIV activity,
palmitic acid may prove an effective treatment for those suffering with
chronic infection.
2.3.6.4. Lectins. At least three different lectins bind HIV glycoproteins
to prevent syncytia formation. In a study conducted by O'Keefe et al., the
lectin cyanovirin-N (CVN) from the cyanobacterium Nostoc ellipsosporum
showed high affinity for gp120 and prevented syncytia formation in vitro
(Table 10) [91]. Another study supported this result, demonstrating that
CVN prevented syncytia formation. However, concentrations required
to prevent syncytia formation were ten-fold higher than those required
to inhibit cell-free virus [218]. CVN irreversibly bound to gp120,
exerting direct virustatic activity, and is thus a potentially useful multimechanism anti-HIV agent. In this study and others, CVN did not show
cytotoxicity but did induce low levels of T-cell proliferation and cytokine release, suggesting that overuse of CVN might have an inflammatory effect. In a different study, the lectin microvirin (MVN) isolated
from the cyanobacterium Microcystis aeruginosa prevented syncytia
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D. Reynolds et al.
gp41, and gp160, most critically preventing interaction between gp120
and the cellular CD4 receptor [220]. One additional study determined
that an aqueous extract of the cyanobacterium Arthrospira platensis had
anti-HIV activity and prevented syncytium formation. While this
investigation did not isolate a specific bioactive compound, the authors
suggest the bioactivity may be due to the presence of a lectin [227].
2.3.6.5. Ulvan. Aguilar-Briseño et al. examined the effect of ulvan from
Ulva clathrata on NDV infection in vitro [134]. NDV relies on a fusion (F)
protein to infect cells. The cleavage of F into F1 and F2 facilitates the
aggregation of target cells into giant syncytia which increases the speed
and efficiency of NDV infection. Ulvan prevented F protein cleavage,
which prevented syncytia formation downstream. Ulvan did not have
any direct virucidal or virustatic action (Table 10).
2.3.6.6. Allophycocyanin. Apoptosis is an endogenous mechanism
involving programmed cell death commonly used by the body to slow
the spread of viral infection. However, some viruses can take advantage
of apoptosis, inducing this mechanism to hasten their own release into
the environment [25]. Shih et al. determined that the pigment protein
allophycocyanin extracted from the cyanobacterium Spirulina (Arthrospira) platensis prevents apoptosis induced by EV71 in vitro using Vero
and human rhabdomyosarcoma cell lines [160]. Due to EV71 infecting
and destroys cells of the nervous system that are not easily replenished,
allophycocyanin might be an especially important therapeutic agent.
2.3.6.7. Durvillaea antarctica polysaccharide. Xu et al. found that polysaccharides extracted from the brown alga (Phaeophyceae) Durvillaea
antarctica prevented EV71-induced apoptosis in vitro using Vero cells
[221]. The administration of D. antarctica polysaccharides downregulated the p53 signaling pathway, which EV71 uses to induce
apoptosis. Furthermore, D. antarctica polysaccharides upregulated
STAT1 and mTOR which are important cell signaling proteins during
EV71 infection. These polysaccharides were also able to decrease inflammatory cytokine production, which are involved in signaling to
initiate apoptosis. Thus, Durvillaea antarctica polysaccharides may be an
important therapeutic agent against EV71.
Fig. 6. Algae-derived compounds prevent viral (I) adhesion, (II) entry and
uncoating, (III) replication, (IV) processing, and (V) budding.
formation between HIV-1-infected T-cells and virus-free CD4+ T-cells in
vitro (Table 10) [219]. While long-term infection did lead to the development of a viral mutant, the mutant was still vulnerable to inhibition
by other lectins. Significantly, the cytotoxicity of MVN was >50-fold
lower than CVN. The lectin griffithsin (GRFT) derived from the red
macroalga Griffithsia also prevents the transmission of HIV via syncytia
formation. In a study conducted by Mori et al., GRFT bound gp120,
Table 11
Algae-derived compounds modulate immune response.
Compound
Species
classification
Species
Virus
Activity
Model
Fucoidan
Phaeophyceae
In
In
In
In
(murine)
(murine)
(murine)
(murine)
[51]
[52]
[211]
[212]
Phaeophyceae
IAV
(H1N1)
IAV, AIV
N/A
N/A
N/A
N/A
N/A
Decrease pathology without affecting viral titer
Stimulate antibody production
Hematopoietic mobilization
Stimulate hematopoiesis
Ascophyllan
HS
Undaria pinnatifida
Undaria pinnatifida
Unknown
Holothuria polii
(sea cucumber)
Ascophyllum nodosum
In vivo (murine)
In vivo (murine)
In vitro
(RAW264.7)
[233]
[234]
[235]
Lipoprotein
Cyanobacteria
Arthrospira platensis
IAV
(H1N1)
In vivo (murine)
In vitro (THP-1)
[236]
[237,238]
Paramylon
Euglenozoa
Euglena gracilis
IAV
(H1N1)
In vivo (murine)
[239]
AEX
Chlorophyta
Coccomyxa
gloeobotrydiformis
IBDV
Stimulate IL-12 production
Upregulate CD40, CD80, CD86, MHCI, MHCII, IL-6, IL12, TNF-α
Promote Th1, Tc1 cell generation, enhance response
Induce DC cell maturation
Stimulate TNF- α, G-CSF, NO production, upregulate
iNOS
Decreased histopathology
Upregulate IL-1β, TNF-α, (IL)–8, MCP-1, MIP-1, MIP-1,
IP-10, COX-2
Increase subject survival rate
Lower viral titer
Upregulate IL-1 β, IL-6, IL-12 (p70), IFN-γ, and IL-10
Increase production of NO
Upregulate IL-1β, IL-6, TNF-α, and iNOS production
Activate PBMCs
Promote extracellular antigen presentation
Promote splenic lymphocyte and DT40 cell proliferation
In vivo (chicken)
[99]
22
vivo
vivo
vivo
vivo
Reference
D. Reynolds et al.
Algal Research 57 (2021) 102331
Fig. 7. Algae-derived compounds stimulate immune response against viral infection. Algae-derived compounds stimulate (I) IFN release, (II) inflammatory response,
(III) cytokine/chemokine production, (IV) antibody production, (V) recruitment of immune system actors including neutrophils, natural killer (NK), and T-cells, and
(VI) dendritic cell maturation.
In a study conducted by Richards et al., an orally administered fucoidan
from the brown (Phaeophyceae) macroalga Undaria pinnatifida
decreased histopathology after influenza infection in a murine model
(Table 11) [51]. Significantly, fucoidan did not decrease the viral titer,
indicating that its beneficial effect could primarily be attributed to antiinflammatory activity or boosting immune response. While we have
discussed reports of direct antiviral effects from fucoidans, it is possible
that their beneficial effects in vivo do not depend entirely on interaction
with the viral replication cycle but rather on protective
immunomodulation.
One other study examined the in vivo immunomodulatory and antiviral effects of a LMW fucoidan from U. pinnatifida [52]. Using a murine
model, fucoidan decreased viral replication and increased antibody
production against two strains of IAV, as well as increasing antibody and
mucosal IgA production against a strain of avian IAV (Table 11). This
result provides strong evidence that fucoidan serves a role in stimulating
the humoral immune response against viral infection.
Fucoidan has shown immunomodulatory effects in other experimental settings. Fucoidan has been investigated as a potential vaccine
adjuvant [240,241]. Investigations have shown that fucoidan is able to
mobilize hematopoietic progenitor cells [231]. Li et al. showed that
fucoidan derived from a sea cucumber increased hematopoiesis in
immunosuppressed mice, increasing white blood cell and neutrophil
counts (Table 11) [232]. Fucoidan may stimulate the migration of white
blood cells and neutrophils from the bone marrow to the bloodstream.
These results show that fucoidan stimulates the immune response and
plays an important role in protecting against viral infection.
2.4. Algae produce immunomodulatory compounds
Immune response to viral infection is immensely complicated,
involving the recruitment of molecular, cellular, and organismal defense
mechanisms [228]. Immune response can be divided into cellular and
humoral components. Humoral immune response to viral infection involves the secretion of antibodies that can directly inhibit viruses or
summon cells of the immune system to phagocytose virions. Cellular
immune response involves the directed killing of infected cells by natural killer or cytotoxic T-lymphocytes [25]. Generally speaking, complex signaling between infected cells and cells of the immune system
initiate protective mechanisms to clear viral infection and protect cells
from harmful pathologies [25,44]. A comprehensive discussion of immune response to viral infection is beyond the scope of this paper.
However, many studies have shown that algae-derived compounds
augment both cellular and humoral immune function against viral
infection, either through direct immunostimulating effects or modulating inflammatory response (Fig. 6). Furthermore, early research has
shown that consumption of algae modifies the profile of host gene
expression with some potential benefits to immune response [229]. In
Section 2.4, we provide an overview of some important immuneactivating properties observed in algae-derived compounds (Table 11,
Fig. 7).
2.4.1. Fucoidan
The polysaccharide fucoidan from brown macroalgae has demonstrated immunomodulatory effects in the prevention of viral infection.
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D. Reynolds et al.
Algal Research 57 (2021) 102331
central role in activating cytotoxic T-lymphocytes (CTLs) which are a
crucial player in adaptive immunity [25]. Thus, the use of AEX as an
immunostimulant may have negative effects in certain situations. This
study also demonstrated that AEX stimulates the differentiation of
lymphocytes. It is important to note that the workings of the immune
system are immensely complex and not comprehensively understood at
this point in time. While it seems that AEX is an immunostimulant, the
discovery that AEX represses MHCI function and lowers viral antibody
titers suggests that the bodily response to AEX is more nuanced than is
currently understood. It seems that AEX has potential as an immunostimulant, vaccine adjuvant, and direct AV drug, but more research is
required to clarify AEX's mechanism.
2.4.2. Ascophyllan HS
Ascophyllan HS is a polysaccharide derived from the brown
(Phaeophyceae) macroalga Ascophyllum nodosum. It is similar to fucoidan, but contains a higher amount of xylose and uronic acid [233]. In a
study conducted by Okimura et al., ascophyllan HS promoted murine
survival in a bacterial respiratory infection model [233]. Mice administered ascophyllan HS showed reduced histopathology and increased
levels of IL-12, indicating that the improved pathology can be attributed
at least in part to stimulation of the immune system (Table 11). Additional research showed that ascophyllan HS induced the activation of
dendritic cells in vitro and in vivo by promoting their production of proinflammatory cytokines. Ascophyllan increased the number of cells
producing IFN, which increases the number of Th1 and Tc1 cells [234].
In this study, ascophyllan facilitated the maturation of dendritic cells, a
crucial part of the adaptive immune response during infection that allows the host organism to develop immunity to a specific pathogen.
In another study, ascophyllan activated macrophages in vitro by
upregulating levels of iNOS expression, inducing the production of nitric
oxide (NO), and increasing production of TNF-α and G-CSF. In this
study, ascophyllan showed greater activation effects than fucoidan with
less cytotoxicity (Table 11) [235]. More research is needed to clarify the
effect of ascophyllan on modulating immune system response against
viral infection. Due to the profound immunostimulatory effects against
other invading pathogens observed in these studies, ascophyllan may
also play a key role in protecting against viral infection.
2.5. Algae produce antioxidant compounds
The immune system often undergoes an oxidative response after viral
infection. Proinflammatory cytokines are important for mobilization of
the immune system against infection. The production of ROS can
encourage proliferation of T-cells. Infection activates phagocytes, which
release proinflammatory cytokines [245]. However, oxidative response
to infection can also be harmful. Some viral replication cycles are promoted by oxidative conditions and overstimulation of the immune system [246,247]. For example, viruses often induce cell death via
apoptosis as a component of their life cycles [245]. Antioxidants can
limit viral replication by preventing apoptosis. Studies have shown that
treatment with antioxidants can alleviate harmful infection pathologies
and limit viral replication [248,249].
Many compounds from algae demonstrate antioxidant abilities.
Sulfated polysaccharides from algae are scavengers of free radicals
[250], so in addition to some of their direct inactivating effects on virions, they may improve clinical outcomes by reducing oxidative
imbalance of infected cells. Phlorotannins have also demonstrated
antioxidant, radical-scavenging ability in addition to their other antiviral activities [251,252]. Furthermore, algae produce many antioxidant
compounds including ascorbate, glutathione, carotenoids (e.g. beta
carotene and astaxanthin), amino acids, catechins, gallate, eckol,
ascorbic acid, and tocopherols that could be incorporated into antiviral
therapies [253,254].
2.4.3. Lipoprotein
Pugh et al. examined the immunostimulatory properties of Immulina®, a commercial extract primarily composed of lipoproteins derived
from the cyanobacterium Arthrospira platensis, and its effect on IAV
infection in a murine model (Table 11) [236]. Mice that were fed a diet
supplemented with the lipoproteins exhibited reduced weight loss,
fewer signs of disease, and improved histopathology scores. Such lipoproteins are immunostimulatory agents and Immulina® has shown the
ability to activate the production of immunoglobulin, interleukins, IFN,
and TNF-α as well as augmenting the innate response of macrophages
and dendritic cells [237,238]. This data suggests that the immunostimulating effects derived from Immulina® are able to protect against
viral infection.
3. Conclusion
2.4.4. Euglena gracilis
Euglenophyceae is a unique class of excavate microalgae. Euglena
gracilis is cultivated as a food and as a supplement. Paramylon is a
polysaccharide found in Euglena gracilis that is used as a primary means
of carbohydrate storage. Nakashima et al. examined the immunoprotective effect of Euglena gracilis and paramylon against IAV in vivo
(Table 11) [239]. Paramylon and Euglena consumed as dietary supplements both increased production of interleukins, TNF, and IFNs,
increased survival rates in mice, and lowered viral titers. It seems the
beneficial effects were mediated by the activation of dendritic cells and
induction of CD8+ T-cells and/or natural killer (NK) cells.
On October 22, 2020, roughly 10 months after the first confirmed
case of COVID-19 on US shores, the FDA approved the first drug to be
used as treatment for COVID-19. This drug, known as remdesivir (RDV)
and marketed under the name Veklury is manufactured by Gilead Sciences Inc. [255]. The initial announced cost of RDV will be from $2340–
$3120 depending on geographical location and healthcare system provider [256]. RDV potently inhibits the MERS-CoV RNA-dependent RNApolymerase enzyme, supporting the notion that it may also be a useful
therapeutic against SARS-CoV-2 [257]. RDV was shown in one US trial
to significantly reduce recovery times by 33.3% compared to placebo
but has not demonstrated the ability to reduce mortality among infected
COVID-19 patients [258]. In WHO trials, neither RDV nor the other
proposed COVID treatments hydroxychloroquine, lopinavir, or IFN-β1a
reduced mortality, initiation of ventilation treatment, or hospitalization
duration [259].
Clearly there is a need for antiviral compounds that can be quickly
deployed to confront pandemics. As we encounter novel pathogens, we
need readily accessible sources of medicine that can provide additional
protection to prevent some of their most harmful effects. Natural compounds operate through a myriad of different mechanisms and may be
cost-effective solutions to this problem. Due to their incredible diversity,
algae represent a relatively untapped source of such natural compounds.
In recent studies, algae-derived compounds have shown potential as
anti-SARS-CoV-2 agents. These compounds act at different points during
SARS-CoV-2 pathogenesis. Clinical trials examining the therapeutic
2.4.5. Polysaccharide AEX
The acidic polysaccharide AEX, isolated from the green (Chlorophyte) microalga Coccomyxa gloeobotrydiformis, was shown to have
immunomodulatory effects (Table 11). Guo et al. examined the effects of
AEX on immune response in chickens against infectious bursal disease
virus (IBDV) [242]. Investigators found that the administration of AEX
upregulated pro-inflammatory and T-helper cell differentiation cytokines as well as increasing production of nitric oxide (NO) in peripheral
blood mononuclear cells (PBMCs). These effects are important components of immune response to viral infection [243]. In splenic lymphocytes, AEX was also found to repress major histocompatibility complex I
(MHCI). This is an interesting result, as recent research indicates that
MHCI can exacerbate viral infections despite its important role in host
adaptive immunity [244]. It is important to note that MHCI plays a
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D. Reynolds et al.
potential of a carrageenan-based anti-SARS-CoV-2 nasal spray are underway in the USA, with similar research taking place in the UK [70,71].
Thus, algae-derived compounds may serve as a prophylactic measure,
similar to wearing a mask, to prevent SARS-CoV-2 infection by preventing virions from entering the respiratory tract. In Section 2.2, we
discussed algae-derived compounds that can inhibit viruses as they pass
through the vasculature. SARS-CoV-2 viremia is associated with severe
clinical outcomes [80], but lectins derived from algae show bioavailability when introduced into the blood and are potential direct inactivators of SARS-CoV-2 virions [260]. At the cellular level, several
polysaccharides derived from algae have potential to prevent SARSCoV-2 adhesion to target receptors. Fucoidan, glucuronomannan and
sulfated galactofucan have all shown the ability to block interactions
between the SARS-CoV-2 S-protein and cell surface receptors [133,261].
Recently, molecular docking analysis showed that polyphenols extracted from land plants are potential inhibitors of SARS-CoV-2 RDRP [202].
Algae are also prolific producers of polyphenols, and so compounds from
algae may be able to block this important step in the viral replication
cycle. The compound caulerpin from green (Chlorophyte) algae has
recently shown promise as an inhibitor of the SARS-CoV-2 3CL protease
[126]. By interfering with this enzyme, caulerpin may be a safe, effective
blocker of SARS-CoV-2 replication. Furthermore, because SARS-CoV-2 is
associated with a severe inflammatory response [262], antioxidant
compounds from algae may also serve an important role in alleviating
some harmful pathologies during the course of treatment [203]. Accumulating evidence indicates that algae-derived compounds may be able
to make up broad-spectrum, multi-mechanism therapies that potently
and economically inhibit SARS-CoV-2 infection. Deploying such treatment plans may prove an effective way to manage viral outbreaks on a
large scale.
In this review, we examined stages in the viral replication cycle and
discussed how compounds derived from algae inhibit viral infection and
replication at each stage. We discussed many prophylactic compounds
that can be topically applied to prevent viral entry into the body. These
compounds are important to emphasize as easily accessible preventative
measures that can reduce the need for clinical intervention and all the
expenses of intensive medical care. We discussed how some viruses are
transported through the body by way of the lymph and blood before they
reach their target tissue and discussed a few mechanisms that algaederived compounds can use to counter infection at this stage. Certain
compounds from algae show the ability to directly interact with and
degrade virions as they travel through the vasculature or augment the
activities of phagocytes, the body's mobile defense system. We further
discussed viral replication at the cellular level and mentioned compounds derived from algae that have the ability to limit infection during
adhesion, entry, uncoating, replication, processing, and release. Many
synthetic drugs operate at individual stages of the replication process;
due to the diversity of natural compounds there is exceptional potential
for developing multi-target treatment plans that could work throughout
the infection cycle to limit viral replication. We further discussed the
body's natural immune response to infection. We mentioned an array of
algae-derived compounds that have demonstrated the ability to
augment this immune response via a series of complex pathways and
mechanisms. Intimately related to the immune response is the oxidative
response to infection. While a thorough analysis of intra- and extracellular redox states during infection is beyond the scope of this paper, we
mentioned algae-derived compounds that can reduce harmful oxidative
effects associated with viral infection.
Natural products adapted for medicinal purposes can have powerful
downstream health benefits in the human body. Gueven et al. performed
research using human subjects and showed that the oral administration
of fucoidan from the brown (Phaeophyceae) macroalga Undaria pinnatifida affected the expression of 53 micro-RNAs in the hours and days
following consumption [229]. These micro-RNAs have been implicated
in diverse functions throughout the human body relating to immune
function, cell growth and division, inflammation, and neurological
control. Health effects derived from the administration or consumption
of algae-based compounds are complex but likely profound.
While it has grown somewhat in recent years, the scope of algaeantiviral literature is quite limited. Nevertheless, we have shown how
a diverse array of algae-derived compounds can prevent against viral
infection at the various stages of pathogenesis. In this review we
demonstrated that species from all the major groups of algae have shown
antiviral effects against a similarly broad diversity of viruses. The
exceptional potential demonstrated by the existing literature represents
the tip of an iceberg. There are certainly many more yet-unobserved
compounds that could play a crucial part in controlling harmful widespread diseases through direct antiviral action, augmentation of protective endogenous biological pathways, or further processing and
chemical modification to form effective semi-synthetic therapeutics.
More research should be performed on antiviral compounds derived
from algae and other natural sources, as such investigations might yield
many life-saving drugs.
CRediT authorship contribution statement
Daman Reynolds: Conceptualization, Investigation, Writing –
Original Draft, Visualization.
Michael Huesemann: Conceptualization, Writing – Review &
Editing, Supervision, Project Supervision.
Scott Edmundson: Conceptualization, Writing – Review & Editing,
Supervision.
Amy Sims: Writing – Review & Editing.
Brett Hurst: Writing – Review & Editing.
Sherry Cady: Writing – Review & Editing.
Nathan Beirne: Investigation.
Jacob Freeman: Investigation.
Adam Berger: Investigation.
Song Gao: Investigation.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgment
This work was supported in part by the U.S. Department of Energy,
Office of Science, Office of Workforce Development for Teachers and
Scientists (WDTS) under the Science Undergraduate Laboratory Internships Program (SULI).
A portion of the research described in this paper was conducted
under the Laboratory Directed Research and Development Program at
Pacific Northwest National Laboratory, a multiprogram national laboratory operated by Battelle for the U.S. Department of Energy.
Informed consent, human/animal rights
No conflicts, informed consent, or human or animal rights are
applicable to this study.
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