Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of SARS-CoV-2 Variants of Concern
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Abstract
New variants of SARS-CoV-2 with potential for enhanced transmission, replication, and immune evasion capabilities continue to emerge causing reduced vaccine efficacy and/or treatment failure. As of January 2021, the WHO has defined five ‘variants of concern’ (VOC): B.1.1.7 (Alpha, α), B.1.351 (Beta, β), P.1 (Gamma, γ), B.1.617.2 (Delta, δ), and B.1.1.529 (Omicron, o). To provide a therapeutic option for the treatment of COVID-19 and variants, Nirmatrelvir, the antiviral component of PAXLOVID™, an oral outpatient treatment recently authorized for conditional or emergency use treatment of COVID-19, was developed to inhibit SARS-CoV-2 replication. Nirmatrelvir (PF-07321332) is a specific inhibitor of coronavirus main protease (Mpro, also referred to as 3CLpro), with potent antiviral activity against several human coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS (Owen et al, Science 2021. doi: 10.1126/science.abl4784). Here, we evaluated PF-07321332 against the five SARS-CoV-2 VOC (α, β, γ, δ,, o) and two Variants of Interest or VOI, C.37 (λ) and B.1.621 (μ), using qRT-PCR in VeroE6 cells lacking the P-glycoprotein (Pgp) multidrug transporter gene (VeroE6 P-gp knockout cells). Nirmatrelvir potently inhibited USA-WA1/2020 strain, and α, β, γ, λ, δ, μ, and o variants in VeroE6 P-gp knockout cells with mean EC 50 values 38.0 nM, 41.0 nM, 127.2 nM, 24.9 nM, 21.2 nM, 15.9 nM, 25.7 nM and 16.2 nM, respectively. Sequence analysis of the Mpro encoded by the variants showed ~100% identity of active site amino acid sequences, reflecting the essential role of Mpro during viral replication leading to ability of Nirmatrelvir to exhibit potent activity across all the variants.
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SciScore for 10.1101/2022.01.17.476644: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources All SARS-CoV-2 viruses were propagated by infecting 70-90% confluent Vero E6 TMPRSS2 cells in a T225 cell culture flask in viral growth media (DMEM supplemented with 1 mg/ml geneticin and 10% FBS) at 37°, 5% CO2. Vero E6 TMPRSS2suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)Cell culture and EC50 assay: The Vero E6 cell line consisting of a knockout in the P glycoprotein (P-gp) multidrug transporter gene (MDR1) was generated by Synthego Corp at the request of Pfizer … SciScore for 10.1101/2022.01.17.476644: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources All SARS-CoV-2 viruses were propagated by infecting 70-90% confluent Vero E6 TMPRSS2 cells in a T225 cell culture flask in viral growth media (DMEM supplemented with 1 mg/ml geneticin and 10% FBS) at 37°, 5% CO2. Vero E6 TMPRSS2suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)Cell culture and EC50 assay: The Vero E6 cell line consisting of a knockout in the P glycoprotein (P-gp) multidrug transporter gene (MDR1) was generated by Synthego Corp at the request of Pfizer as a contract service (VeroE6 P-gp knock out (KO) cells, manuscript in preparation). Vero E6suggested: RRID:CVCL_XD71)The VeroE6-PgP-ko cells were maintained in a complete growth medium (DMEM supplemented with 1% antibiotic – antimycotic and 10% FBS). VeroE6-PgP-kosuggested: NoneSoftware and Algorithms Sentences Resources Copy number values were used to calculate percent inhibition of viral replication by Remdesivir or Nirmatrelvir in Excel using the calculation: percent inhibition = 100*((No drug copy number-sample copy no.)/No drug copy number). Excelsuggested: NoneEC50 and EC90 values for both compounds for each virus were calculated in GraphPad Prism using the log(inhibitor) vs. response—Variable slope (four parameters) and [Agonist] vs. response-Find ECanything parameters, respectively. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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