COVID-19 Treatment Idea: Ultra-Executive Summary

COVID-19 treatment idea
March 28, 2020
Ultra-Executive Summary
Hypothesis: Substantially increasing protein intake could work as a treatment for COVID-19. More
sophisticated variations on this idea could also work. If true, this would provide a cheap and “already-
deployed” remedy for COVID-19.
Executive Plain-English Summary

Hypothesis:
Most current COVID-19 drugs coincidentally share a common substructure. This substructure allows
them to do a job that people are overlooking. This job may be the actual reason they work, or it may
supplement the “main” mechanism of action. Knowing this, we can nd other “drugs” with this “special
structure” that can do this “overlooked job.”
When protein is digested, it breaks down into smaller pieces called peptides. Some peptides have the
“special structure” to do the “overlooked job.”
SARS-CoV-2, the virus behind COVID-19, works by entering healthy cells and hijacking their machinery
to make more viruses. To enter the cell, SARS-CoV-2 needs to grab onto the cell. There is a special “handle”
that SARS-CoV-2 grabs onto. The “handle” is on the outside of an enzyme called ACE2. The “overlooked
job” is to make it so that SARS-CoV-2 cannot grab onto the “handle.” But this “overlooked job” is done in
an unexpected way.
The “normal activity” of ACE2 is to “process” certain peptides. When ACE2 “processes” these peptides,
it looks like a clamshell clamping down on whatever is on the inside (normally, certain speci c peptides
are on the inside). This “clamshell motion” causes the outside of ACE2 to become warped/distorted; that
means that the handle is also warped/distorted. This distortion is what makes the virus unable to grab on.
The “special structure” of current COVID-19 drugs allows them to also induce the clamshell motion.
Brief Technical Summary

Hypothesis:
Many drugs supposedly showing e cacy against SARS-CoV-2 may at least partially bene t from an
overlooked mechanism of action. Namely, the drugs act as ACE2 inhibitors which, upon binding to the
catalytic active site of ACE2, induce a substantial conformational change. This “protected conformation”
is substantially less suitable for S protein binding (which takes place on the “outside” of ACE2 rather than
inside the ACE2 catalytic active site cleft where inhibitors/substrates bind).
If this is true, then rst of all, drug design/screening can target the(/one of the) actual MOA.
Furthermore, perhaps it is possible to treat COVID-19 with simple peptides which are suitable as sub-
strates for ACE2. If used in great enough abundance, then these benign (and even nutritious) peptides would
increase engagement of ACE2, thereby acting as quasi-inhibitors which induce the protected conformation.
(It is of course necessary that the kinetics of the underlying processes be appropriate.)
Extended Technical Summary

• The S proteins of SARS-CoV-1 and SARS-CoV-2 both bind to ACE2.1,2
1
• Binding for SARS-CoV-1 is known to take place on the “outside” of ACE2,1 which may leave the ACE2
catalytic active side una ected. It is presumed that SARS-CoV-2 does as well.
• Upon substrate/inhibitor binding to ACE2 at the catalytic active site, ACE2 undergoes a “substantial”
conformational change (“clamshell” 16° hinge-bending of the two sides of the active site cleft).3
– Pantoliano and coworkers speculate in the last paragraph of their report3 that this conformational
change may be enough to provide protection from SARS binding.
∗ No prior precedent is cited in this report to support this speculation.
∗ None of the papers from 2020 which cite this report make mention of this speculative possi-
bility for a “protected conformation.”
• Many of the small-molecule drugs known to be under exploration4 share a particular motif: an amide-
like nitrogen connected to a chain of four atoms that then splits into two branches on the fth chain
atom (Figure 1).
– Chloroquine is a conveniently simple representation.
– At least one of the two branches is “short” (e.g., methyl or ethyl).
– This substructure seems as though it would be appropriate for some degree of binding the ACE2
cataltyic active site.
∗ The crude superimposition of chloroquine over a depiction of the ACE2-bound inhibitor from
the Pantoliano report3 roughly illustrates how this might happen (Figure 2).
∗ Particularly relevant is the “S1 subsite” of ACE2 described by Pantoliano and coworkers, which
contains a small pocket under the “Tyr510 lid.”3
· Importantly, this pocket is most suitable for substrates like angiotensin II, but is less
e ective for angiotensin I due to the presence of the bulkier His residue at the P1 position
in angiotensin II.3 This suggests that angiotensin I might act as a quasi-inhibitor for ACE2
in context of inducing the “protected conformation.”
• Thus, might it be possible to attempt to treat COVID-19 through the use of simple peptides?
– One example of a peptide known to be hydrolyzed by ACE2 is β-casomorphin,5 so a derivative of
milk might help.
– However, in order to decrease clearance burden and the risk of side e ects, it might be best to
use speci c di-/triipeptides.
∗ Based on the way that angiotensin I has good binding to ACE2 but is hydrolyzed with a
catalytic e ciency orders of magnitude lower than angiotensin II, it seems as though peptides
with His as the second to last amino acid (C-terminus end) might be especially e ective.
∗ It may be possible to use combinations of di erent peptides to create an “extended release”
e ect (i.e., di erent amino acid sequences and di erent peptide lengths).
– It may be possible that rate of protein digestion would be enough to provide an extended release.
– Delivery methods other than simple digesion (e.g., intravenous) may also be viable.
• If true, the role of diet in COVID-19 vulnerability might be much greater than currently assumed.
2
Figure 1: Selection of drug molecules currently being explored for COVID-19 treatment; relevant submotifs are high-
lighted.
Figure 2: Crude superimposition of chloroquine and angiotensin II over an ACE2-bound inhibitor (partly adapted from
Pantoliano and coworkers3 ).
3
References
(1) Wu, K.; Peng, G.; Wilken, M.; Geraghty, R. J.; Li, F. Mechanisms of Host Receptor Adaptation by
Severe Acute Respiratory Syndrome Coronavirus. J. Biol. Chem. 2012, 287 (12), 8904–8911. https:
//doi.org/10.1074/jbc.M111.325803.
(2) Ho mann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T. S.;
Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2
and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 0 (0), ASAP. https://doi.org/10
.1016/j.cell.2020.02.052.
(3) Towler, P.; Staker, B.; Prasad, S. G.; Menon, S.; Tang, J.; Parsons, T.; Ryan, D.; Fisher, M.; Williams,
D.; Dales, N. A.; et al. ACE2 X-Ray Structures Reveal a Large Hinge-Bending Motion Important for
Inhibitor Binding and Catalysis. J. Biol. Chem. 2004, 279 (17), 17996–18007. https://doi.org/10.107
4/jbc.M311191200.
(4) Philippidis, A. Catching Up to Coronavirus: Top 60 Treatments in Development https://www.gene

ngnews.com/virology/coronavirus/catching-up-to-coronavirus-top-60-treatments-in-development/ (ac-
cessed Mar 23, 2020).
(5) Jiang, F.; Yang, J.; Zhang, Y.; Dong, M.; Wang, S.; Zhang, Q.; Liu, F. F.; Zhang, K.; Zhang, C.
Angiotensin-Converting Enzyme 2 and Angiotensin 1–7: Novel Therapeutic Targets. Nat. Rev. Cardiol.
2014, 11 (7, 7), 413–426. https://doi.org/10.1038/nrcardio.2014.59.

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COVID-19 treatment idea

March 28, 2020

Executive Plain-English Summary

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Extended Technical Summary

(4) Philippidis, A. Catching Up to Coronavirus: Top 60 Treatments in Development https://www.gene

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