Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

Iketani, Sho; Mohri, Hiroshi; Culbertson, Bruce; Hong, Seo Jung; Duan, Ying; Luck, Maria I; Annavajhala, Medini K.; Guo, Yicheng; Sheng, Zizhang; Uhlemann, Anne‐Catrin; Goff, Stephen P.; Sabo, Yosef; Yang, Haitao; Chavez, Alejandro; Ho, David D.

doi:10.1038/s41586-022-05514-2

Cited by 195 publications

(309 citation statements)

References 54 publications

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“…Despite extensive resistance profiling attempts 10,40,51 , no viral escape from molnupiravir has yet been reported, whereas pe-existing paxlovid resistance mutations have been detected in some circulating SARS-CoV-2 strains that are considered able to spread 42,52 . However, whole genome sequencing of virus population isolated from paxlovid-experienced ferrets provided no evidence that replication rebound and transmission both from and to paxlovid-treated animals in our study were supported by emerging resistance to nirmatrelvir 41-43 . Alternatively, poor control of upper respiratory infection and failure to prevent transmission could be due to lower nirmatrelvir exposure in upper respiratory tissues than lung or changing upper respiratory exposure profiles after repeat dosing.…”

Section: Discussioncontrasting

confidence: 73%

“…Whole genome sequencing of virus populations in nasal lavage and turbinate samples taken from these animals revealed that most had acquired an N501T or Y453F substitution in the Spike protein that are characteristic for SARS-CoV-2 adaptation to replication in mustelids 23 (extended data Fig. 3), but no signature resistance mutation to nirmatrelvir in nsp5 [41][42][43] emerged as allele dominant (uploaded as NCBI BioProject PRJNA894555). At study end, infectious titers and viral RNA copies in nasal turbinate tissues were statistically significantly reduced in paxlovid-treated animals compared to the vehicle group (Fig.…”

Section: Paxlovid Treatment Of Sars-cov-2 Infection In Ferretsmentioning

confidence: 99%

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Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

Cox

Lieber

Wolf

et al. 2022

Preprint

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Despite the continued spread of SARS-CoV-2 and emergence of variants of concern (VOC) that are capable of escaping preexisting immunity, therapeutic options are underutilized. In addition to preventing severe disease in high-risk patients, antivirals may contribute to interrupting transmission chains. The FDA has granted emergency use authorizations for two oral drugs, molnupiravir and paxlovid. Initial clinical trials suggested an efficacy advantage of paxlovid, giving it a standard-of-care-like status in the United States. However, recent retrospective clinical studies suggested a more comparable efficacy of both drugs in preventing complicated disease and case-fatalities in older adults. For a direct efficacy comparison under controlled conditions, we assessed potency of both drugs against SARS-CoV-2 in two relevant animal models; the Roborovski dwarf hamster model for severe COVID-19 in high-risk patients and the ferret model of upper respiratory tract disease and transmission. After infection of dwarf hamsters with VOC omicron, paxlovid and molnupiravir were efficacious in mitigating severe disease and preventing death. However, a pharmacokinetics-confirmed human equivalent dose of paxlovid did not significantly reduce shed SARS-CoV-2 titers in ferrets and failed to block virus transmission to untreated direct-contact ferrets, whereas transmission was fully suppressed in a group of animals treated with a human-equivalent dose of molnupiravir. Prophylactic administration of molnupiravir to uninfected ferrets in direct contact with infected animals blocked productive SARS-CoV-2 transmission, whereas all contacts treated with prophylactic paxlovid became infected. These data confirm retrospective reports of similar therapeutic benefit of both drugs for older adults, and reveal that treatment with molnupiravir, but not paxlovid, may be suitable to reduce the risk of SARS-CoV-2 transmission.

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Section: Discussioncontrasting

confidence: 73%

Section: Paxlovid Treatment Of Sars-cov-2 Infection In Ferretsmentioning

confidence: 99%

Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

Cox

Lieber

Wolf

et al. 2022

Preprint

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“…While these results support the selection of these mutants in serial passage, there appears to be some discrepancy in the magnitude of resistance between changes in in vitro Ki compared to changes in antiviral EC 50 . This is observed for other M pro variants such as S144A, which is selected in serial passage and has been determined by Pfizer as causing a 90-fold increase in niramtrelvir K i while antiviral studies show a more modest 2-fold increase in antiviral EC 50 ( 30 ). The smaller changes in antiviral EC 50 may result from the fact that M pro has a wide range of affinities ( K d measurements ranging from 28 µM to 2.7 mM) for its different polyprotein cleavage sites ( 33 ).…”

Section: Discussionmentioning

confidence: 84%

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Moghadasi

Heilmann

Khalil³

et al. 2022

Preprint

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First-generation vaccines and drugs have helped reduce disease severity and blunt the spread of SARS-CoV-2. However, ongoing virus transmission and evolution and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease (Mpro/3CLpro) of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional inhibitor in clinical development, ensitrelvir, shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that nirmatrelvir-resisting variants have pre-existed the introduction of this drug into the human population and are capable of spreading. A similarly strong argument can be made for ensitrelvir. These results caution against broad administration of protease inhibitors as stand-alone therapies and encourage the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles.

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“…As antiviral drug resistance is inevitable, it is vital to predict M pro drug-resistant mutants before they become dominant in the clinic. It is gratifying that our genome sequence mining approach identified similar drug-resistant mutants (E166A, E166 V, S144A) in the serial viral passage experiments . The clinical relevance of the high profile mutations identified from our genome mining approach needs to be further characterized using recombinant SARS-CoV-2 viruses in cell culture and animal models.…”

Section: Concluding Remarksmentioning

confidence: 97%

SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies

et al. 2022

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Conspectus SARS-CoV-2 is the etiological pathogen of the COVID-19 pandemic, which led to more than 6.5 million deaths since the beginning of the outbreak in December 2019. The unprecedented disruption of social life and public health caused by COVID-19 calls for fast-track development of diagnostic kits, vaccines, and antiviral drugs. Small molecule antivirals are essential complements of vaccines and can be used for the treatment of SARS-CoV-2 infections. Currently, there are three FDA-approved antiviral drugs, remdesivir, molnupiravir, and paxlovid. Given the moderate clinical efficacy of remdesivir and molnupiravir, the drug–drug interaction of paxlovid, and the emergence of SARS-CoV-2 variants with potential drug-resistant mutations, there is a pressing need for additional antivirals to combat current and future coronavirus outbreaks. In this Account, we describe our efforts in developing covalent and noncovalent main protease (M pro ) inhibitors and the identification of nirmatrelvir-resistant mutants. We initially discovered GC376, calpain inhibitors II and XII, and boceprevir as dual inhibitors of M pro and host cathepsin L from a screening of a protease inhibitor library. Given the controversy of targeting cathepsin L, we subsequently shifted the focus to designing M pro -specific inhibitors. Specifically, guided by the X-ray crystal structures of these initial hits, we designed noncovalent M pro inhibitors such as Jun8-76-3R that are highly selective toward M pro over host cathepsin L. Using the same scaffold, we also designed covalent M pro inhibitors with novel cysteine reactive warheads containing di- and trihaloacetamides, which similarly had high target specificity. In parallel to our drug discovery efforts, we developed the cell-based FlipGFP M pro assay to characterize the cellular target engagement of our rationally designed M pro inhibitors. The FlipGFP assay was also applied to validate the structurally disparate M pro inhibitors reported in the literature. Lastly, we introduce recent progress in identifying naturally occurring M pro mutants that are resistant to nirmatrelvir from genome mining of the nsp5 sequences deposited in the GISAID database. Collectively, the covalent and noncovalent M pro inhibitors and the nirmatrelvir-resistant hot spot residues from our studies provide insightful guidance for future work aimed at developing orally bioavailable M pro inhibitors that do not have overlapping resistance profile with nirmatrelvir.

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Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

Cited by 195 publications

References 54 publications

Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies

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