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

Moghadasi, Seyed Arad; Heilmann, Emmanuel; Khalil, Ahmed Magdy; Nnabuife, Christina; Kearns, Fiona L.; Ye, Chengjin; Moraes, Sofia N; Costacurta, Francesco; Esler, Morgan A.; Aihara, Hideki; Laer, Dorothee von; Martínez-Sobrido, Luis; Palzkill, Timothy; Amaro, Rommie E.; Harris, Reuben S.

doi:10.1101/2022.08.07.503099

Cited by 54 publications

(91 citation statements)

References 67 publications

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“…During our study, multiple preprints have appeared, discussing certain SARS-CoV-2 M pro mutations and their effect on NTV. − The methodologies used in these studies to discover the mutations with resistance potential are diverse, which is reflected in their results. As is observed in our study, previously reported mutational hotspots include the active site of M pro , with special emphasis on the residues S144, E166, L167, and Q192.…”

Section: Discussionmentioning

confidence: 99%

“…Drug resistance to protease inhibitors has previously been reported for several other infectious viral species, − making it prudent to monitor the circulating SARS-CoV-2 variants for early identification of NTV resistance. Indeed, several recent preprints disclose experimentally found M pro variants which reduce the potency of NTV. − These studies encompassed a variety of methodologies, including data mining of SARS-CoV-2 sequences and passage experiments. Especially, substitutions of substrate binding pocket residues such as S144, E166, L167, and Q192 resulted in loss of NTV inhibition (Table S1).…”

Section: Introductionmentioning

confidence: 99%

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Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening

et al. 2022

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The main protease (M pro ) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 M pro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of M pro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of M pro . The E166M mutation reduced the half-maximal inhibitory concentration (IC 50 ) of NTV 24-fold and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening

et al. 2022

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“…During our study, multiple preprints have appeared, discussing certain SARS-CoV-2 M pro mutations and their effect on NTV. [27][28][29][30][31][32][33] The methodologies used in these studies to discover the mutations with resistance potential are diverse, which is reflected in their results. As is observed in our study, previously reported mutational hotspots include the active site of M pro , with special emphasis on the residues S144, E166, L167, and Q192.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several recent preprints disclose experimentally found M pro variants which reduce the potency of NTV. [27][28][29][30][31][32][33] These studies encompassed a variety of methodologies, including data mining of SARS-CoV-2 sequences and passage experiments. Especially substitutions of substrate binding pocket residues such as S144, E166, L167, and Q192 resulted in loss of NTV inhibition (Supporting Information Table 3).…”

Section: Introductionmentioning

confidence: 99%

Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening

Sasi¹,

Ullrich²,

Ton³

et al. 2022

Preprint

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The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mpro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mpro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold, and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.

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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][42][43] .…”

Section: Discussionmentioning

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

Cited by 54 publications

References 67 publications

Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening

Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening

Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening

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

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