7U28

Structure of SARS-CoV-2 Mpro Lambda (G15S) in complex with Nirmatrelvir (PF-07321332)

Summary for 7U28

• Entry DOI: 10.2210/pdb7u28/pdb
• Related: 7TLL
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: protease, sars-cov-2, covalent complex, inhibitor, hydrolase-inhibitor complex, omicron, pf-07321332, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 68714.22

Authors

Greasley, S.E.,Ferre, R.A.,Plotnikova, O.,Liu, W.,Stewart, A.E. (deposition date: 2022-02-23, release date: 2022-03-09, Last modification date: 2022-06-15)

Primary citation

Greasley, S.E.,Noell, S.,Plotnikova, O.,Ferre, R.,Liu, W.,Bolanos, B.,Fennell, K.,Nicki, J.,Craig, T.,Zhu, Y.,Stewart, A.E.,Steppan, C.M.
Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants.
J.Biol.Chem., 298:101972-101972, 2022

PubMed Abstract: The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (M) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the M of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the M specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant M demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant M including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β M at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells.

PubMed: 35461811
DOI: 10.1016/j.jbc.2022.101972

Experimental method

X-RAY DIFFRACTION (1.679 Å)