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The power of similarities to accelerate antiviral development for COVID-19

Posted on January 11th, 2022 by in COVID-19

In April 2020, I wrote a blog post entitled “Exploiting similarities between SARS-CoV-2 and other viruses to accelerate vaccine and therapy development,” where I described research areas leveraging genetic and phenotypic similarities between SARS-CoV-2 and other known viruses. In my quest to find relevant data, I used Reaxys Medicinal Chemistry to generate a list of substances that interact with enterovirus 3C proteases, a target showing striking similarities with the main proteases of SARS-CoV and SARS-CoV-2. A set of interesting derivatives using a cyanohydrin as an anchor group caught my attention.1 Interestingly, Pfizer used the cyano warhead a few months later to design their protease inhibitor (PF-07321332). Pfizer’s antiviral forms a complex structure with SARS-CoV-2 Mpro, demonstrating the efficacy of the cyano warhead to form a covalent bond with the cysteine residue at the active site.2

A few days after I published my first blog post, a preprint (which I missed! at the time) described the striking three-dimensional structural similarity between Hepatitis C virus (HCV) NS3/4A protease and SARS-CoV-2 Mpro protease, particularly in the arrangement of key active site residues.3 Following the power of similarities, PharmaPendium can be used to retrieve marketed drugs targeting HCV-proteases. As part of the few drugs available on the market, Boceprevir is a ketoamide-derived HCV NS3 protease inhibitor used to treat hepatitis caused by HCV genotype 1 and closely structurally related to PF-07321332, the antiviral developed by Pfizer for COVID-19.

You will find above the structures of Boceprevir, PF-07321332, and a cyanohydrin enterovirus 3C protease inhibitor. Even non-chemists can identify similarities (highlighted in green and blue) between these compounds.

A few weeks ago, Pfizer announced in a press release that its EPIC-HR trial ran an interim analysis; it showed an 89% reduction in hospitalization or death when their antiviral PaxlovidTM (PF-07321332 ritonavir) was given to high-risk patients within 3 days of symptom onset, and 85% reduction when given within 5 days. Pfizer has a lot of experience, expertise and data related to antiviral proteases. Their achievement is impressive and is great news for our brawl against COVID-19. 

Interested in leveraging the power of similarities for your research?

The metaphor “standing on the shoulders of giants” is often used to describe research and how researchers depend on the work of others. No matter how new and challenging a situation is, we always need to rely on the data and knowledge produced by those giants. The wealth and depth of data excerpted, normalized, and curated in Elsevier solutions allows you to embrace the power of similarities fully and leverage the data produced by your peers. Please reach out if you need access to a specific dataset to support your analyses or have questions about how we could help you pursue your own research goals. 

[1]. Y. Zhai et al., 10.1021/acs.jmedchem.5b01013 (2015)
[2]. Y. Zhao et al., 10.1007/s13238-021-00883-2
[3]. K. Bafna et al., https://chemrxiv.org/engage/chemrxiv/article-details/60c74a16337d6c5f89e27805

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