Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Noske, G.D.; Silva, Ellen de Souza; Godoy, Mariana Ortiz de; Dolci, Isabela; Fernandes, R.S.; Güido, Rafael Victório Carvalho; Sjö, Peter; Oliva, Glaucius; Godoy, Andre S.

doi:10.1016/j.jbc.2023.103004

Cited by 63 publications

(54 citation statements)

References 45 publications

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“…31 Moreover, Nirmatrelvir resistance has also been reported although it has been on the market for less than one year. [34][35][36][37][38][39][40][41] Therefore, developing more M pro inhibitors with new chemical structures and/or new action modes is necessary.…”

Section: Discussionmentioning

confidence: 99%

“…For example, SARS-CoV-2 viruses carrying M pro mutants E166N/V, M165T, G143S, Q189E, A173V, H172F/Q/Y, or Q192S/T/V are found to be resistant to Paxlovid. [34][35][36][37][38][39][40][41] To predict the ability of SY110 to overcome the drug-resistance, we in this investigation expressed a panel of 14 mutated recombinant M pro ; viruses carrying these M pro mutants are reported to be resistant to Nirmatrelvir. Our data show that SY110 can, to some extent, overcome the Nirmatrelvirresistances caused by mutations at E166N (IC 50 folds: 54.5 vs 336.3) and E166V (IC 50 folds: 17.8 vs 187.3).…”

Section: Discussionmentioning

confidence: 99%

“…E166N/V M165T, G143S, Q189E, A173V, H172F/Q/Y or Q192S/T/V mutation in the M pro was recently shown to be associated with Nirmatrelvir resistance. [34][35][36][37][38][39][40][41] To evaluate the efficacy of SY110 against these mutated M pro , we expressed a panel of 14 mutated recombinant M pro and tested their enzymatic sensitivity to SY110 and Nirmatrelvir by FRET assay. As shown in Fig.…”

Section: Evaluations Of the Drug Metabolism And Pharmacokinetics (Dmpk)mentioning

confidence: 99%

“…Although SY110 also displayed reduced activity against most of these mutants, it exhibited substantially elevated activity against the E166N and E166V mutants, indicating that SY110 can, at least partially, overcome these two kinds of Nirmatrelvir-resistances. A possible explanation for this might be as follows: E166 is a hotspot for Nirmatrelvir-resistant mutation, [34][35][36][37][38][39][40][41] which locates at the S1 pocket. The side chain oxygen of E166 forms 3.2 Å hydrogen bond with lactam ring of Nirmatrelvir.…”

Section: Evaluations Of the Drug Metabolism And Pharmacokinetics (Dmpk)mentioning

confidence: 99%

“…For examples, variants bearing E166N/V, M165T, G143S, Q189E, A173V, H172F/Q/Y, or Q192S/T/V mutants in M pro have been reported to be resistant to Nirmatrelvir treatment. [34][35][36][37][38][39][40][41] Therefore, developing next-generation antivirals is urgent.…”

Section: Introductionmentioning

confidence: 99%

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A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Huang

Shuai

Qiao

et al. 2023

Sig Transduct Target Ther

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Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Evaluations Of the Drug Metabolism And Pharmacokinetics (Dmpk)mentioning

confidence: 99%

Section: Evaluations Of the Drug Metabolism And Pharmacokinetics (Dmpk)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Huang

Shuai

Qiao

et al. 2023

Sig Transduct Target Ther

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Emerging SARS-CoV-2 Resistance After Antiviral Treatment

Tamura,

Choudhary,

Deo

et al. 2024

JAMA Netw Open

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ImportancePrevious studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood.ObjectiveTo examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound.Design, Setting, and ParticipantsThis cohort study enrolled outpatient adults with acute COVID-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicenter health care system in Boston, Massachusetts.ExposureTreatment regimen, including none, nirmatrelvir, and remdesivir.Main Outcomes and MeasuresThe primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant’s treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population.ResultsOverall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants’ anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (&lt;20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorization of nirmatrelvir.Conclusions and RelevanceIn this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.

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Assessing the inhibition efficacy of clinical drugs against the main proteases of SARS‐CoV‐2 variants and other coronaviruses

Zhao,

Lupala,

Hou

et al. 2024

Quant. Biol.

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Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Cited by 63 publications

References 45 publications

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Emerging SARS-CoV-2 Resistance After Antiviral Treatment

Assessing the inhibition efficacy of clinical drugs against the main proteases of SARS‐CoV‐2 variants and other coronaviruses

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