Exploiting similarities between SARS-CoV-2 and other viruses to accelerate vaccine and therapy development

Posted on April 17th, 2020 by Paul Dockerty in COVID-19

Coronavirus disease 19 (COVID-19) is now
present in 230 countries, areas or territories around the world. As of April 15,
2020, the World Health Organization has reported 117,021 deaths [1].
Researchers across the globe are collaborating to develop antivirals and
vaccines. In this context, understanding the vast amount of data published on
SARS-CoV and other viruses is key to tackling the challenge of containing the
2019 novel coronavirus (SARS-CoV-2).

Genetic and phenotypic similarities between
SARS-CoV-2 and other known viruses can highlight research areas worth pursuing.
Here I’d like to discuss three examples:

• The main proteases of the
  original SARS-CoV and SARS-CoV-2
  show striking similarities and drugs targeting the protease of the first could
  be effective against the second
• By the
  same token, feature similarities between the SARS-CoV main protease and the 3C
  proteases of enteroviruses could be exploited as effective drug target sites
• Finally,
  overlap in binding sites of antibodies studied for SARS-CoV may point to
  effective vaccines for the current pandemic

These comparisons based on knowledge about
known viruses require data that have been normalized across sources, which is a
key feature of Reaxys Medicinal Chemistry (RMC) data on substance pharmacokinetics,
toxicity, safety, metabolic profile and target affinity. Thus, a few weeks ago
we identified 393 substances in RMC that interact with 25 targets related
to six target species and coronavirus groups (SARS-CoV, Middle East respiratory
syndrome [MERS] coronavirus, human coronavirus 229E, Coronaviridae, and
Coronavirinae) with an affinity of <1 mM.

The list included
substances containing characteristic covalent warheads such as α-ketoamide, Michael acceptors or aldehydes that, given the possibly
high similarity between SARS-CoV and SARS-CoV-2, were likely to be potent
binders of the SARS-CoV-2 main protease. This possibility was confirmed on March 20,
2020 in a Science publication [2] showing the X-ray structures of the
unliganded protease SARS-CoV-2 M^pro (which shares 96% sequence
identity with SARS-CoV M^pro) and its complex with an α-ketoamide
inhibitor. The inhibitor showed lung tropism in mice and could be nebulized for
direct administration to the lungs where the virus thrives.

Similarities between coronaviruses and enteroviruses are also insightful. The main protease of coronaviruses and the 3C protease of enteroviruses have a similar active site. I used RMC to quickly generate a list of 148 substances that interact with enterovirus 3C proteases. Among the most potent inhibitors in the resulting list, derivatives using cyanohydrin as an anchor group quickly emerged as an intriguing option for SARS-CoV-2 M^pro [3] considering their demonstrated affinity and selectivity for EV71 3C^pro and SARS-CoV-M^pro. If you’re interested in seeing this list of substances, please contact me directly.

Conserved domains among
viruses are particularly interesting for the structure-based design of
therapeutics [4] and the development of vaccines. On April 3, 2020 a group from The
Scripps Research Institute demonstrated that an antibody recovered from a survivor
of the SARS epidemic reacts with SARS-CoV-2 [5]. The
antibody’s binding site on the two coronaviruses differs by only four amino acids.
These findings can help develop treatments for COVID-19 and hint at
vulnerabilities that we could exploit to fight coronaviruses in general and
avoid future pandemics.

Catalyzing these types of insights was our
goal in creating the Coronavirus
Research Repository with ¹science. Mirroring the mission of ¹science
to aggregate quality-controlled academic and research documents in all
disciplines and languages and from all countries, and leveraging its core index
¹findr with >120 million metadata records and >30 million
links to free full-text articles from roughly 100,000 referred scholarly
journals, the Coronavirus
Research Repository is a custom extraction comprising articles on
COVID-19, MERS, SARS and coronaviruses in general.

So, where do you go next?

The list of 393 substances
and other potential antivirals identified in the first example are on the Resources for drug discovery section of our Elsevier Coronavirus Information Center page.

If you would like to see the list of 148 drugs I extracted by comparing coronaviruses and enteroviruses, please contact me directly.

Finally, I am also happy to help if you need access to other datasets for your COVID-19 research, or have questions about how to pursue the insights I’ve described and take advantage of the datasets we have made available.

References:

[1] WHO – Situation report 85

[2] L. Zhang et al., Science 10.1126/science.abb3405 (2020)

[3] Y. Zhai et al., 10.1021/acs.jmedchem.5b01013 (2015)

[4] L. Zhang et al., J. Med. Chem. 10.1021/acs.jmedchem.9b01828 (2020)

[5] M. Yuan et al., Science 10.1126/science.abb7269 (2020)

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