H172Y mutation perturbs the S1 pocket and nirmatrelvir binding of SARS-CoV-2 main protease through a nonnative hydrogen bond
de Oliveira et al.,
H172Y mutation perturbs the S1 pocket and nirmatrelvir binding of SARS-CoV-2 main protease through a nonnative..,
Research Square, doi:10.21203/rs.3.rs-1915291/v1 (Preprint) (In Vitro)
In Silico and In Vitro study of the H172Y mutation which significantly reduces paxlovid's inhibitory activity. Monotherapy with paxlovid and selective pressure may favor resistance mutations.
de Oliveira et al., 9 Aug 2022, preprint, 5 authors.
Contact:
jana.shen@rx.umaryland.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: H172Y mutation perturbs the S1 pocket and
nirmatrelvir binding of SARS-CoV-2 main protease
through a nonnative hydrogen bond
Vinicius de Oliveira
University of Maryland School of Pharmacy
Mohamed Ibrahim
University of Luebeck
Xinyuanyuan Sun
University of Luebeck
Rolf Hilgenfeld
University of Luebeck
Jana Shen ( jana.shen@rx.umaryland.edu )
University of Maryland School of Pharmacy https://orcid.org/0000-0002-3234-0769
Article
Keywords:
Posted Date: August 9th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-1915291/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.
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H172Y mutation perturbs the S1 pocket and
nirmatrelvir binding of SARS-CoV-2 main
protease through a nonnative hydrogen bond
Vinicius Martins de Oliveira,† Mohamed Fourad Ibrahim,‡ Xinyuanyuan
Sun,‡ Rolf Hilgenfeld,‡,¶ and Jana Shen∗,†
† Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy,
Baltimore, Maryland, USA
‡ Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany
¶ German Center for Infection Research (DZIF), Hamburg – Lübeck – Borstel – Riems
Site, University of Lübeck, Lübeck, Germany
E-mail: jana.shen@rx.umaryland.edu
1
Abstract
Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro)
and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID19 patients. Although the prevalent Mpro mutants in the SARS-CoV-2 Variants of
Concern (e.g., Omicron) are still susceptible to nirmatrelvir, a rare natural mutation,
H172Y, was found to significantly reduce nirmatrelvir’s inhibitory activity. As the selective pressure of antiviral therapy may favor resistance mutations, there is an urgent
need to understand the effect of the H172Y mutation on Mpro’s structure, function,
and drug resistance. Here we report the molecular dynamics (MD) simulations as
well as the measurements of stability, enzyme kinetics of H172Y Mpro, and IC50 value
of nirmatrelvir. Simulations showed that mutation disrupts the interactions between
the S1 pocket and N terminus of the opposite protomer. Intriguingly, a native hydrogen bond (H-bond) between Phe140 and the N terminus is replaced by a transient
H-bond between Phe140 and Tyr172. In the ligand-free simulations, strengthening of
this nonnative H-bond is correlated with disruption of the conserved aromatic stacking
between Phe140 and His163, leading to a partial collapse of the oxyanion loop. In the
nirmatrelvir-bound simulations, the nonnative H-bond is correlated with the loss of an
important H-bond between Glu166 and nirmatrelvir’s lactam nitrogen at P1 position.
These results are consistent with the newly reported X-ray structures of H172Y Mpro
and suggest a mechanism by which the H172Y substitution perturbs the S1 pocket,
leading to the decreased structural stability and binding affinity, which in turn explains
the drastic reduction in catalytic activity and antiviral susceptibility.
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