Study suggests efficacy of SARS-CoV-2 main protease inhibitors is not compromised in current COVID-19 variants

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has significantly impacted the healthcare system and the global economy. To date, COVID-19 has claimed more than 5.21 million lives worldwide.

Study: Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332. Image Credit: Kateryna Kon/ShutterstockStudy: Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332. Image Credit: Kateryna Kon/Shutterstock

Background

In response to the pandemic, scientists worldwide have worked at a record speed to develop effective vaccines and therapeutics. Scientists believe that effective COVID-19 vaccines are the only effective mean that can bring down the mortality rate, the transmission of the virus and eventually aid in containing the pandemic. At present, several COVID-19 vaccines have received emergency use authorization (EUA), and, subsequently, vaccination programs have commenced in many countries.

All the currently available COVID-19 vaccines have been developed based on the spike protein of the original SARS-CoV-2 strain that had first emerged in Wuhan in China in 2019. However, owing to the evolution of the virus, where many of the mutations are found in the spike region, scientists are skeptical about the efficacy of the existing COVID-19 vaccines against the newly emerged variants.

The newly emerged SARS-CoV-2 variants have been categorized as variants of concern (VOC) and variants of interests (VOI). Some VOCs are Alpha, Beta, Gamma, and Delta, and VOIs are Lambda and Mu. At present, the designs of vaccines have been modified such that they remain effective against all the variants. 

Effectiveness of antiviral drugs against SARS-CoV-2 infection

Another important measure to minimize the mortality rate due to SARS-CoV-2 infection is the development of antiviral drugs. Some of the common drug targets that have been identified are RNA-dependent RNA polymerase (RdRp, nsp12), the helicase (nsp13), the papain-like protease (PLpro, part of nsp3), and the main protease (Mpro, 3CLpro, nsp5).

Recently, the orally active drug molnupiravir was approved in the United Kingdom for COVID-19 treatment. This drug targets RdRp by acting as a nucleoside analog prodrug; however, this was originally developed against different RNA viruses. Another drug that has recently attracted much attention as a potential COVID-19 drug is the peptidomimetic PF-07321332 (Paxlovid™ as a combination drug with ritonavir as a booster). Currently, this compound has entered phase 3 clinical trials. 

Scientists have characterized SARS-CoV-2 Mpro as a homodimeric cysteine protease, comprising the majority of the viral polyproteins pp1a and pp1ab. This protein is encoded by SARS-CoV-2’s ORF1a/b gene. Previous studies have revealed that PF-07321332 is an orally available Mpro inhibitor that contains a nitrile warhead that covalently binds the catalytic cysteine residue present in the active site of the protease. Inhibition of Mpro would ultimately block the assembly of the replication and transcription complexes (RTCs). Early research on SARS-CoV-1 Mpro had reported that missense point mutations could affect protease activity. 

Assessment of the efficacy of PF-07321332 against SARS-CoV-2 variants

A new study, published on the bioRxiv* preprint server, has focussed on assessing the Mpro mutants of newly emerged SARS-CoV-2 variants. The authors of this study characterized the amino acid substitutions in SARS-CoV-2 Mpro by enzyme kinetics. They further determined their susceptibility to inhibition by PF-07321332. 

Scientists analyzed the genomes of SARS-CoV-2 lineages of both VOCs and VOIs, using the database operated by Scripps Research. In this study, the WIV04 sequence was considered as the wildtype reference genome.

The genomic comparison between VOIs and VOCs revealed the presence of two missense mutations, i.e., G15S and K90R, in the Mpro section of the ORF1a/b gene that occurred at a frequency above 20%. The Delta variant, which is the dominant strain circulating currently, did not exhibit the presence of missense mutations within the Mpro part of ORF1a/b. This study also investigated three additional abundant Mpro mutations to include more lineages T21I, L89F, L205V.

All the five selected mutations that are mostly present in various SARS-CoV-2 lineages were further considered for X-ray crystal structures analysis. Baring T21I, all other mutations exhibited no major changes in the chemical character of the side-chains. T21I displayed only moderate change.

The Förster resonance electron transfer (FRET) in vitro assay of Mpro activity was used to evaluate the initial velocities of the proteolytic activity at various substrate concentrations. This analysis showed that all mutants are enzymatically active as a dysfunctional Mpro would inhibit SARS-CoV-2 replication. The kinetic analysis, as well as FRET assay, confirmed the efficacy of PF-07321332 for inhibiting the activity of Mpro variants at nanomolar compound concentrations. Importantly, the degree of inhibition was found to be similar across the different protease variants.

Conclusion

The authors of this study have identified the most prevalent Mpro variants in different lineages of SARS-CoV-2. Most importantly, this study determined the efficacy of PF-07321332 against all the Mpro variants. In the past, protease inhibitors have demonstrated their effectiveness in treating various viral diseases, such as HIV and HCV. Therefore, scientists are optimistic that Mpro inhibitors would have a similar effect on the treatment of SARS-CoV-2 infection. 

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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