Resistance to nirmatrelvir due to mutations in the Mpro in the subvariants of SARS-CoV-2 Omicron: Another concern?
2023; Cell Press; Volume: 32; Linguagem: Inglês
10.1016/j.omtn.2023.03.013
ISSN2162-2531
AutoresSrijan Chatterjee, Manojit Bhattacharya, Kuldeep Dhama, Sang‐Soo Lee, Chiranjib Chakraborty,
Tópico(s)COVID-19 Clinical Research Studies
ResumoThe world has faced 3 years of the COVID-19 pandemic with billions of infections, millions of deaths, and a massive economic crisis. Since the pandemic began, scientists have started to fight against SARS-CoV-2. One significant scientific effort was searching for successful therapeutic molecules against the virus. The repurposing of the drug candidates was initiated in the initial stage of the pandemic.1Cantini F. Goletti D. Petrone L. Najafi Fard S. Niccoli L. Foti R. Immune therapy, or antiviral therapy, or both for COVID-19: a systematic review.Drugs. 2020; 80: 1929-1946Crossref PubMed Scopus (71) Google Scholar,2Chakraborty C. Sharma A.R. Bhattacharya M. Agoramoorthy G. Lee S.S. The drug repurposing for COVID-19 clinical trials provide very effective therapeutic combinations: lessons learned from major clinical studies.Front. Pharmacol. 2021; 12: 704205Crossref PubMed Scopus (56) Google Scholar,3Saha R.P. Sharma A.R. Singh M.K. Samanta S. Bhakta S. Mandal S. Bhattacharya M. Lee S.S. Chakraborty C. Repurposing drugs, ongoing vaccine, and new therapeutic development initiatives against COVID-19.Front. Pharmacol. 2020; 11: 1258Crossref PubMed Scopus (84) Google Scholar Along with drug repurposing, new molecule discovery was started by exploring the drug targets. The most significant drug targets are RdRp, Mpro/3CLpro, and others.4More S.A. Patil A.S. Sakle N.S. Mokale S.N. Network analysis and molecular mapping for SARS-CoV-2 to reveal drug targets and repurposing of clinically developed drugs.Virology. 2021; 555: 10-18Crossref PubMed Scopus (15) Google Scholar,5Chakraborty C. Bhattacharya M. Mallick B. Sharma A.R. Lee S.S. Agoramoorthy G. SARS-CoV-2 protein drug targets landscape: a potential pharmacological insight view for the new drug development.Expet Rev. Clin. Pharmacol. 2021; 14: 225-238Crossref PubMed Scopus (15) Google Scholar The possible repurposed and newly discovered therapeutic molecules have been tested in vivo, in vitro, and through clinical trials. They found several effective therapeutic molecules against this virus, such as nirmatrelvir, ritonavir, remdesivir, molnupiravir, etc. One recent effective drug against the SARS-CoV-2 Omicron variant and its subvariant is Paxlovid, which combines two therapeutic molecules (nirmatrelvir and ritonavir). Paxlovid shows high effectiveness against SARS-CoV-2 emerging variants and subvariants.6Ledford H. Maxmen A. African clinical trial denied access to key COVID drug Paxlovid.Nature. 2022; 604: 412-413Crossref PubMed Scopus (9) Google Scholar,7Callaway E. COVID rebound is surprisingly common - even without Paxlovid.Nature. 2022; (Preprint at)https://doi.org/10.1038/d41586-022-02121-zCrossref Google Scholar,8Niraj N. Mahajan S.S. Prakash A. Sarma P. Medhi B. 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Infect. Public Health. 2022; 15: 1234-1258Crossref PubMed Scopus (10) Google Scholar The phenomenon of therapeutic escape causes immense concern to scientists. Recently, several mutations have been noted in Mpro/3CLpro, which might be responsible for the nirmatrelvir resistance (Figure 1). SARS-CoV-2 has acquired a wide range of mutations in its non-structural proteins during its variant generation. They have allowed it to adjust quickly to the environment, increase its infectivity rate, and eventually develop drug resistance due to several mutations in the hotspot residues. This is actually for its survival. The FDA has approved the nirmatrelvir molecule (an antiviral component of Paxlovid) for treating mild-to-moderate infections to combat the developing variations predominantly observed in Omicron and its subvariants.18Padhi A.K. Tripathi T. Hotspot residues and resistance mutations in the nirmatrelvir-binding site of SARS-CoV-2 main protease: design, identification, and correlation with globally circulating viral genomes.Biochem. Biophys. Res. Commun. 2022; 629: 54-60Crossref PubMed Scopus (12) Google Scholar It has been proven that the oral antiviral nirmatrelvir, which targets the 3CL protease of SARS-CoV-2, is clinically effective against the COVID-19 pandemic.19Iketani S. Mohri H. Culbertson B. Hong S.J. Duan Y. Luck M.I. Annavajhala M.K. Guo Y. Sheng Z. Uhlemann A.C. et al.Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir.Nature. 2023; 613: 558-564Crossref PubMed Scopus (63) Google Scholar This drug interacts with the Cys145 residue of the SARS-CoV-2 nsp5 by establishing a covalent bond.20Lan S. Neilsen G. Slack R.L. Cantara W.A. Castaner A.E. Lorson Z.C. Lulkin N.D. Zhang H. Lee J. Cilento M.E. Tedbury P.R. Nirmatrelvir resistance in SARS-CoV-2 Omicron_BA.1 and WA1 replicons and escape strategies.bioRxiv. 2023; (Preprint at)https://doi.org/10.1101/2022.12.31.522389Crossref Scopus (0) Google Scholar New SARS-CoV-2 variants that potently evade the currently available therapeutics continue to arise due to the intense selective pressure against the spike glycoprotein. Many sublineages from Omicron have been reported so far.21Willett B.J. Grove J. MacLean O.A. Wilkie C. De Lorenzo G. Furnon W. Cantoni D. Scott S. Logan N. Ashraf S. et al.SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway.Nat. Microbiol. 2022; 7: 1161-1179Crossref PubMed Scopus (161) Google Scholar,22Greaney A.J. Starr T.N. Gilchuk P. Zost S.J. Binshtein E. Loes A.N. Hilton S.K. Huddleston J. Eguia R. 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Because of its vital role in coronavirus replication, the nsp5 protease found in SARS-CoV-2 and other coronaviruses makes it an extremely promising therapeutic target.21Willett B.J. Grove J. MacLean O.A. Wilkie C. De Lorenzo G. Furnon W. Cantoni D. Scott S. Logan N. Ashraf S. et al.SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway.Nat. Microbiol. 2022; 7: 1161-1179Crossref PubMed Scopus (161) Google Scholar During the SARS pandemic in 2002 and the more recent SARS-CoV-2 pandemic, the major protease (Mpro/3CLpro) of the coronavirus (CoV) family was initially investigated as a target for designing various therapeutics.25Anand K. Ziebuhr J. Wadhwani P. Mesters J.R. Hilgenfeld R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs.Science. 2003; 300: 1763-1767Crossref PubMed Scopus (1359) Google Scholar,26Boras B. Jones R.M. Anson B.J. Arenson D. Aschenbrenner L. Bakowski M.A. Beutler N. Binder J. Chen E. Eng H. et al.Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.Nat. Commun. 2021; 12: 6055Crossref PubMed Scopus (130) Google Scholar,27Service R.F. A call to arms.Science. 2021; 371: 1092-1095Crossref PubMed Scopus (7) Google Scholar The successful results obtained by constructing protease inhibitors for the hepatitis C virus (HCV) and HIV-1 virus instigated the development of a similar therapeutic to treat SARS-CoV-2 virus infection.28Flexner C. HIV-protease inhibitors.N. Engl. J. Med. 1998; 338: 1281-1292Crossref PubMed Scopus (772) Google Scholar,29Anderson J. Schiffer C. Lee S.K. Swanstrom R. Viral protease inhibitors.Handb. Exp. Pharmacol. 2009; 189: 85-110Crossref PubMed Scopus (94) Google Scholar SARS-CoV-2 viruses now in circulation have Mpro mutations that make them resistant to nirmatrelvir. For instance, the M49I mutation was discovered in 1,883 genomes in May 2022, with a minor increase in late 2021.30Sedova M. Jaroszewski L. Iyer M. Godzik A. Monitoring for SARS-CoV-2 drug resistance mutations in broad viral populations.bioRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.05.27.493798Crossref Google Scholar Sasi et al. highlighted that the potency of nirmatrelvir is decreased by five mutations, namely Q189E, Q192T, N142L, Q189I, and E166M. The IC50 of nirmatrelvir was reduced by a factor of 24 against the E166M mutation.31Sasi V.M. Ullrich S. Ton J. Fry S.E. Johansen-Leete J. Payne R.J. Nitsche C. Jackson C.J. Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening.Biochemistry. 2022; 61: 2495-2505Crossref PubMed Scopus (11) Google Scholar According to phylogenetic analyses, nirmatrelvir-resistant variants are transmissible and appear to have existed before nirmatrelvir was introduced into the human population.32Moghadasi S.A. Heilmann E. Moraes S.N. Kearns F.L. von Laer D. Amaro R.E. et al.Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.bioRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.08.07.503099Crossref PubMed Scopus (0) Google Scholar In addition, Lan et al.20Lan S. Neilsen G. Slack R.L. Cantara W.A. Castaner A.E. Lorson Z.C. Lulkin N.D. Zhang H. Lee J. Cilento M.E. Tedbury P.R. Nirmatrelvir resistance in SARS-CoV-2 Omicron_BA.1 and WA1 replicons and escape strategies.bioRxiv. 2023; (Preprint at)https://doi.org/10.1101/2022.12.31.522389Crossref Scopus (0) Google Scholar designed specific mutations to hinder nirmatrelvir’s ability to attach to its substrate to study nirmatrelvir resistance. They used 12 wild-type SARS-CoV-2 replicons and one subvariant of the Omicron (BA.1), followed by specific enzymatic assays and cell-based complementation. The result demonstrated that E166V conferred strong nirmatrelvir resistance, approximately 55-fold, with a significant drop in wild-type replicon fitness (nearly 20-fold), but not in the BA.1 subvariant (2-fold), in both cases. However, L50F improved the fitness of wild-type replicons. Due to these variations, Omicron possibly may have a lower resistance barrier than the wild-type variant.20Lan S. Neilsen G. Slack R.L. Cantara W.A. Castaner A.E. Lorson Z.C. Lulkin N.D. Zhang H. Lee J. Cilento M.E. Tedbury P.R. 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First, the trial participants received treatment when the infection was still in its early stages. In practice, it can be challenging to administer antivirals to patients as soon as they are diagnosed as positive. Second, despite careful patient selection, nirmatrelvir monotherapy produces suboptimal clinical results.37Mahase E. Covid-19: pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports.BMJ. 2021; 375: n2713Crossref PubMed Scopus (249) Google Scholar,38Jayk Bernal A. Gomes da Silva M.M. Musungaie D.B. Kovalchuk E. Gonzalez A. Delos Reyes V. Martín-Quirós A. Caraco Y. Williams-Diaz A. Brown M.L. et al.Molnupiravir for oral treatment of covid-19 in Nonhospitalized patients.N. Engl. J. Med. 2022; 386: 509-520Crossref PubMed Scopus (839) Google Scholar Nirmatrelvir has been shown to reduce viral infection in hamsters’ respiratory organs after they are infected by the BA.2 variant.39Uraki R. Kiso M. Iida S. Imai M. Takashita E. Kuroda M. Halfmann P.J. Loeber S. Maemura T. Yamayoshi S. et al.Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2.Nature. 2022; 607: 119-127Crossref PubMed Scopus (112) Google Scholar The transmission of the virus was suppressed entirely in a group of animals given a human-equivalent dose of molnupiravir. Still, a pharmacokinetic human-equivalent dose of nirmatrelvir did not significantly lower the SARS-CoV-2 titers in ferrets. It also did not prevent viral transmission to untreated ferrets in direct contact. While the prophylactic nirmatrelvir treatment resulted in an infection in all contacts, prophylactic molnupiravir treatment of uninfected ferrets close to the infected group prevented SARS-CoV-2 transmission.40Cox R.M. Lieber C.M. Wolf J.D. Karimi A. Lieberman N.A.P. Sticher Z.M. Roychoudhury P. Andrews M.K. Krueger R.E. Natchus M.G. et al.Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets.bioRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.08.07.503099Crossref Scopus (0) Google Scholar An analysis by Iketani et al.19Iketani S. Mohri H. Culbertson B. Hong S.J. Duan Y. Luck M.I. Annavajhala M.K. Guo Y. Sheng Z. Uhlemann A.C. et al.Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir.Nature. 2023; 613: 558-564Crossref PubMed Scopus (63) Google Scholar of 13 recombinant SARS-CoV-2 clones revealed that higher levels of resistance needed the accumulation of further mutations, because three noteworthy mutations, namely T21I, P252L, and T304I, caused only low-level resistance. The most significant resistance was acquired by the E166V mutation (nearly 100-fold). However, this mutation also reduced the ability of the virus to replicate, which was later recovered by compensatory modifications like T21I and L50F. The results also show that the viral resistance to nirmatrelvir can quickly develop in vitro through a variety of pathways, and the unique mutations found here provide a solid framework to investigate the mechanism of resistance in more detail and guide the development of potent protease inhibitors in future generations.19Iketani S. Mohri H. Culbertson B. Hong S.J. Duan Y. Luck M.I. Annavajhala M.K. Guo Y. Sheng Z. Uhlemann A.C. et al.Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir.Nature. 2023; 613: 558-564Crossref PubMed Scopus (63) Google Scholar According to molecular dynamics simulations, a combination of L50F with E166M, and E166V alone, reduced the binding efficacy between nirmatrelvir and Mpro. The polymerase inhibitor remdesivir and bebtelovimab (a monoclonal antibody) maintained their anti-nirmatrelvir activity against the emerging resistant lineages. However, a combination of these compounds with nirmatrelvir has shown to be more effective compared with the administration of the individual components. These discoveries affect how therapies for the SARS-CoV-2 virus are monitored and ensured to be effective.41Zhou Y. Gammeltoft K.A. Ryberg L.A. Pham L.V. Tjørnelund H.D. Binderup A. Duarte Hernandez C.R. Fernandez-Antunez C. Offersgaard A. Fahnøe U. et al.Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system.Sci. Adv. 2022; 8: eadd7197Crossref PubMed Scopus (35) Google Scholar The quick and aggressive preclinical development of nirmatrelvir helped reduce the health care burden due to the COVID-19 pandemic in 2022. This drug has shown to be exceptionally efficient in combating the Omicron wave, with preserved in vitro and clinical efficacy. In the first quarter of 2022, nirmatrelvir generated $1.5 billion in sales, making it one of the most common antivirals prescribed throughout the world.42Gold J.A.W. Kelleher J. Magid J. Jackson B.R. Pennini M.E. Kushner D. Weston E.J. Rasulnia B. Kuwabara S. Bennett K. et al.Dispensing of oral antiviral drugs for treatment of COVID-19 by zip code-level social vulnerability - United States, december 23, 2021-may 21, 2022.MMWR Morb. Mortal. Wkly. Rep. 2022; 71: 825-829Crossref PubMed Google Scholar When this drug is taken, the immune system actively destroys the virus, including any potentially resistant versions that may have developed. It makes sense to concentrate efforts on surveillance of immunocompromised patients receiving nirmatrelvir treatment to detect the emergence of a drug-resistant virus. If medication resistance could be chosen in vitro, as has happened previously with other viral infections, it will undoubtedly produce similar results in vivo. Although most of the existing COVID-19 treatments have been given as monotherapies, it is feasible that future treatments can be beneficial by employing a drug cocktail to reduce the possibility of SARS-CoV-2 escape.19Iketani S. Mohri H. Culbertson B. Hong S.J. Duan Y. Luck M.I. Annavajhala M.K. Guo Y. Sheng Z. Uhlemann A.C. et al.Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir.Nature. 2023; 613: 558-564Crossref PubMed Scopus (63) Google Scholar Therefore, scientists need to work on other drug cocktails and discover more antiviral molecules to increase the therapeutic options for treating emerging variants and subvariants of SARS-CoV-2. Simultaneously, it would hinder drug resistance by the SARS-CoV-2 variants and subvariants and help to reduce the health care burden due to the ongoing COVID-19 pandemic. The authors confirm that the data supporting the findings of this study are available within the article.
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