Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development
<p>The malaria parasite life cycle. <span class="html-italic">Plasmodium</span> sporozoites are injected into the human host’s dermis during an <span class="html-italic">Anopheles</span> mosquito blood meal before making their way to the liver. Hepatic schizogony begins when a sporozoite invades a hepatocyte, and the resultant merozoites (10<sup>4</sup>) enter the bloodstream to start the symptomatic ABS characterized by the presence of 10<sup>9</sup>–10<sup>11</sup> parasites in total. A small percentage of asexual parasites engage in gametocytogenesis, producing adult male and female gametocytes (10<sup>7</sup>–10<sup>9</sup> in total) in a development process that lasts 10–12 days. Roughly 103 gametocytes are transmitted to <span class="html-italic">Anopheles</span> mosquitoes following a blood meal. The midgut of the mosquito activates gametogenesis, which is followed by fertilization to form a diploid zygote, which, during meiosis, elongates into a tetraploid ookinete within ~24 h. Ookinetes develop in six morphologically distinct stages and progress to oocysts (~48 h) by penetrating the midgut wall. Each oocyst (1–5 in total) is attached to the basal lamina of the midgut and replicates its genome for the next 6–12 days to develop hundreds of sporozoites inside the cellular membrane (sporogony). The cycle is restarted when sporozoites develop and migrate to the salivary glands of the mosquito to infect another human host. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>.</p> "> Figure 2
<p>An overview of the most common transmission-blocking assays showing their targets in the <span class="html-italic">Plasmodium</span> life cycle. Viability assays are employed to assess the influence of potential drugs on gametocyte development. The DGFA is used to evaluate the ability of compounds to inhibit the production of gametes. The SMFA is employed to assess the transmission-blocking potential of drug candidates. In its indirect form, the SMFA informs on the effect of small molecules on <span class="html-italic">Plasmodium</span> gametocytogenesis, whereas in its direct version, it informs on the impact on gamete development into the oocyst. The ODA (* performed in <span class="html-italic">P. berghei</span>) enables the assessment of the effects of potential drugs on the early sporogonic development of parasites in the mosquito midgut. DGFA—dual gamete formation assay; ODA—ookinete development assay; SMFA—standard membrane feeding assay. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>.</p> "> Figure 3
<p>Structures and transmission-blocking activities of compounds <b>1</b>–<b>7</b> currently in clinical phases.</p> "> Figure 4
<p>Structures and biological activities of epigenetic inhibitors <b>20</b>–<b>25</b> identified by Coetzee et al. as transmission-blocking antiplasmodial agents.</p> "> Figure 5
<p>Structures and transmission-blocking activities of compounds <b>12a</b>–<b>c</b> and <b>26a</b>,<b>b</b> developed from HDAC inhibitors.</p> "> Figure 6
<p>Structures and transmission-blocking activities of KDM inhibitors <b>11a</b>, <b>27</b>, <b>28a</b>,<b>b</b> (<b>A</b>), and <b>29a</b>–<b>e</b> (<b>B</b>).</p> "> Figure 7
<p>Structures and transmission-blocking activities of kinase inhibitors <b>30</b>, <b>31</b>, <b>32a</b>,<b>b</b>, <b>33a</b>–<b>d</b>, and <b>34</b>.</p> "> Figure 8
<p>(<b>A</b>) The structure and transmission-blocking activity of the YRS inhibitor ML901 (<b>35</b>). (<b>B</b>) Structures, transmission-blocking activities, and SARs of the most relevant N-4HCS <b>36a</b>,<b>b</b>.</p> "> Figure 9
<p>Development, chemical structures, transmission-blocking activities, and mode of action of iPanAms <b>37a</b>–<b>e</b>.</p> "> Figure 10
<p>(<b>A</b>) Structures and transmission-blocking activities of compounds <b>38a</b>–<b>c</b> targeting microtubule assembly. (<b>B</b>) Structures and transmission-blocking activities of compounds inhibiting plasmepsins IX and X (<b>39</b>) and <span class="html-italic">Pf</span>20S proteasome (<b>40a</b>,<b>b</b>).</p> "> Figure 11
<p>Structures and transmission-blocking activities of compounds <b>41</b>–<b>45</b> (<b>A</b>) and NBDHEX (<b>46a</b>) and its metabolite NBDHEX-COOH (<b>46b</b>) (<b>B</b>).</p> "> Figure 12
<p>(<b>A</b>) Structures, SARs, and transmission-blocking activities of compounds <b>47a</b>–<b>c</b>. (<b>B</b>) Structures and transmission-blocking activities of compounds <b>48a</b>–<b>c</b>, <b>49</b>, and <b>50</b>.</p> "> Figure 13
<p>Structures and biological transmission-blocking activities of compounds <b>51</b>–<b>55</b>.</p> "> Figure 14
<p>(<b>A</b>) Atovaquone (<b>56</b>) structure and transmission-blocking activities. (<b>B</b>) Schematic of the atovaquone-coated-surface approach developed by Paton et al. [<a href="#B145-pharmaceuticals-17-00962" class="html-bibr">145</a>]. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>.</p> ">
Abstract
:1. Introduction
2. The Transmission-Blocking Screening Landscape
2.1. Gametocytocidal Assays
2.2. Dual Gamete Formation Assay (DGFA)
2.3. SMFA
2.4. Sporogonic Development Assays Using P. berghei
3. Transmission-Blocking Antimalarial Drugs
3.1. Transmission Blockers in Clinical Development
3.2. Epigenetic Transmission-Blocking Drugs
3.3. Antiplasmodial Transmission-Blocking Compounds Inhibiting Plasmodium Kinases
3.4. Aminoacyl-tRNA Synthetase Inhibitors
3.5. Pfs16 Inhibitors
3.6. Acetyl Coenzyme a Synthesis Inhibitors
3.7. Transmission-Blocking Compounds Altering Microtubule Assembly, Plasmepsins IX and X, and Pf20S Proteasome
3.8. Drug Repurposing as an Approach to Developing Transmission-Blocking Compounds
3.9. Multistage Active Drugs with Unknown Targets
3.10. Innovative Approaches: Atovaquone-Coated Surfaces to Block Parasite Transmission
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ABSs | Asexual blood stages |
Ac-COA | Acetyl coenzyme A |
ACS | Acyl-CoA synthetase |
AMS | Adenosine-5′-sulfamate |
aaRSs | Aminoacyl-tRNA synthetases |
ATP | Adenosine triphosphate |
BCKDH | Branched-chain keto-dehydrogenase |
CETSA | Cellular thermal shift assay |
CYP | Cytochrome P450 |
DGFA | Dual gamete formation assay |
DMSO | Dimethyl sulfoxide |
DNMT | DNA methyltransferase |
EC50 | 50% effective concentration |
ED90 | 90% effective dose |
EIA | Exflagellation inhibition assay |
EM | Electron microscopy |
ETC | Electron transport chain |
FGAA | Female gamete activation assay |
G6PD | Glucose-6-phosphate dehydrogenase |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
GFP | Green fluorescent protein |
GST | Glutathione S-transferase |
HDAC | Histone deacetylase |
HEA | Hydroxyethylamine |
HMT | Histone methyltransferase |
IAP | Inhibitor of apoptosis |
IC50 | 50% inhibitory concentration |
IF | Immunofluorescence |
iPanAms | Inverted pantothenamides |
JmjC | Jumonji C |
KDM | Lysine demethylase |
LDH | Lactate dehydrogenase |
MMV | Medicines for Malaria Venture |
ODA | Ookinete development assay |
PABP1 | Polyadenylate-binding protein 1 complex |
PCNA1 | Proliferating cell nuclear antigen |
PfCLK3 | P. falciparum cyclin-dependent-like kinase |
PfDHFR | P. falciparum dihydrofolate reductase |
PfATP4 | P. falciparum Na+-efflux ATPase ATP4 |
PfPANK1 | P. falciparum pantothenate kinase 1 |
PfPI4Kβ | P. falciparum phosphatidylinositol 4-kinase type III β |
PfeEF2 | P. falciparum translation elongation factor 2 |
PfYRS | P. falciparum tyrosine-tRNA synthetase |
PfvapA | P. falciparum V-type H + -ATPase |
Pf20S | P. falciparum 20S proteasome |
PheRS | Phenylalanyl-tRNA synthetase |
PK | Pharmacokinetics |
PM | Plasmepsins |
PMIX | Plasmepsin IX |
PMX | Plasmepsin X |
PVM | Parasitophorous vacuole membrane |
RBCs | Red blood cells |
SAHA | Suberoylanilide hydroxamic acid |
SaLSSA | Saponin-lysis sexual stage assay |
SAR | Structure–activity relationship |
SMFA | Standard membrane feeding assay |
SPR | Surface plasmon resonance |
TAP | Triaminopyrimidine |
YRS | Tyrosine-tRNA synthetase |
WHO | World Health Organization |
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Compound | Structure | Target Class | Asexual IC50 ± SEM (nM) | Stage I–II Gametocyte IC50 ± SEM (nM) | Stage IV–V Gametocyte IC50 ± SEM (nM) |
---|---|---|---|---|---|
SGI-1027 8 | DNMT | 50.8 ± 0.6 | 18.2 ± 2.1 | 322.4 ± 123.7 | |
Chaetocin 9 | HMT | 775.3 ± 366.0 | 292.3 ± 25.7 | 504.5 ± 92.3 | |
BIX01294 10a | HMT | 10.5 ± 3.6 | 12.3 ± 1.3 | 939.0 ± 84.7 | |
UNC0631 10b | HMT | 28.5 ± 5.9 | 14.8 ± 0.9 | 641.2 ± 83.0 | |
UNC0642 10c | HMT | 19.2 ± 10.4 | 14.6 ± 0.8 | 929.6 ± 199.0 | |
UNC0379 10d | HMT | 50.4 ± 2.3 | 21.3 ± 4.8 | >1000 | |
UNC0638 10e | HMT | 21.6 ± 2.0 | 16.4 ± 1.0 | >1000 | |
UNC0646 10f | HMT | 140.1 ± 3.8 | 66.8 ± 22.6 | >1000 | |
JIB-04 11a | KDM | 470.5 ± 28.3 | 133.1 ± 18.5 | 262.5 ± 113.0 | |
Quisinostat 12a | HDAC | <13 | <13 | 148.1 ± 145.8 | |
Panobinostat 13 | HDAC | 8.7 ± 3.8 | 12.0 ± 4.8 | 515.3 ± 144.7 | |
Apicidin 14 | HDAC | 23.1 ± 15.2 | 103.6 ± 2.9 | 590.2 ± 146.6 | |
HC Toxin 15 | HDAC | 15.1 ± 3.7 | 30.2 ± 0.1 | 351.4 ± 221.3 | |
CUDC-101 16 | HDAC | 35.6 ± 8.4 | 133.1 ± 6.3 | 2150.4 ± 744.3 | |
Trichostatin A 17 | HDAC | 62.3 ± 21.1 | 53.9 ± 5.4 | 3795.5 ± 1576.3 | |
Dacinostat 18 | HDAC | 40.8 ± 19.1 | 45.3 ± 0.9 | 2266.1 ± 843.2 | |
Fedratinib 19 | Kinase | 66.9 ± 2.8 | 96.9 ± 19.7 | >1000 |
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Appetecchia, F.; Fabbrizi, E.; Fiorentino, F.; Consalvi, S.; Biava, M.; Poce, G.; Rotili, D. Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development. Pharmaceuticals 2024, 17, 962. https://doi.org/10.3390/ph17070962
Appetecchia F, Fabbrizi E, Fiorentino F, Consalvi S, Biava M, Poce G, Rotili D. Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development. Pharmaceuticals. 2024; 17(7):962. https://doi.org/10.3390/ph17070962
Chicago/Turabian StyleAppetecchia, Federico, Emanuele Fabbrizi, Francesco Fiorentino, Sara Consalvi, Mariangela Biava, Giovanna Poce, and Dante Rotili. 2024. "Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development" Pharmaceuticals 17, no. 7: 962. https://doi.org/10.3390/ph17070962