Abstract:The Omicron variant of the SARS-CoV-2 virus was first detected in South Africa in November 2021. The analysis of the sequence data in the context of earlier variants suggested that it may show very different characteristics, including immune evasion and increased transmission. These assumptions were partially confirmed, and the reduction in protection in convalescent patients and vaccinated individuals have been confirmed. Here, we have evaluated the efficacy of antivirals against SARS-CoV-2 variants, Omicron,… Show more
“…Therefore, it is not surprising that the observed activity of Nirmatrelvir against these variants was relatively similar. In agreement with our report, two independent groups [14,17] reported that Nirmatrelvir is active against SARS-CoV-2 VOC, further supporting the efficacy of the drug against the circulating SARS-CoV-2 variants, including Omicron. N=number; *=mathematical average (N=2) a. EC50 values for Nirmatrelvir against variants were evaluated using a one-way ANOVA (with USA-WA1 as the fixed effect) and Dunnett test, the p values for the alpha, beta, gamma, lambda and delta variants were 0.9838, 0.0479, 0.9794, 0.8433 and 0.5213, respectively.…”
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 PAXLOVIDTM, 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 EC50 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.
“…Therefore, it is not surprising that the observed activity of Nirmatrelvir against these variants was relatively similar. In agreement with our report, two independent groups [14,17] reported that Nirmatrelvir is active against SARS-CoV-2 VOC, further supporting the efficacy of the drug against the circulating SARS-CoV-2 variants, including Omicron. N=number; *=mathematical average (N=2) a. EC50 values for Nirmatrelvir against variants were evaluated using a one-way ANOVA (with USA-WA1 as the fixed effect) and Dunnett test, the p values for the alpha, beta, gamma, lambda and delta variants were 0.9838, 0.0479, 0.9794, 0.8433 and 0.5213, respectively.…”
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 PAXLOVIDTM, 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 EC50 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.
“…These described biochemical/biophysical results are in line with the equivalent antiviral potency of these molecules against WT and Omicron and the lack of observable differences in the active site. 5 – 8 Fig. 1 Biochemical and structural comparison of WT and Omicron M pro P132H.…”
“…These described biochemical/biophysical results are in line with the equivalent antiviral potency of these molecules against WT and Omicron and the lack of observable differences in the active site. 4-7…”
The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and is considered to be one of the most promising SARS-CoV-2 drug targets. While Mpro mutations have occurred in many variants, including Omicron (B.1.1.529), their structural and biochemical importance have, until this point, remained uncharacterized. Using X-ray crystallography, we show the Omicron Mpro mutant (P132H) induces a small rearrangement of residues distal from the active site. While enzymatic activity and small-molecule inhibition appears unchanged, the melting temperature (Tm) of Omicron Mpro is 2.6 ° C lower than Alpha and Delta Mpro. Yet, when incubated with inhibitors, these enzymes have nearly identical Tm values. The physiological importance of the P132H mutant is unclear; however, we show residue 132 is located at the interface of the dimerization and catalytic domains and is frequently mutated in other variants. Lower thermal stability may indicate increased flexibility that can potentially broaden substrate profile or alter inhibitor binding. Therefore, structural insights are key to anticipating future mutations that may promote drug-resistance and are especially important at present, given the recent approval of nirmatrelvir (PAXLOVID), an oral SARS-CoV-2 Mpro inhibitor.
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