SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. - Archive ouverte HAL Access content directly
Journal Articles Nature Microbiology Year : 2021

SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution.

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Mark G Lewis
  • Function : Author
Hanne Andersen
  • Function : Author

Abstract

Humans can be infected by SARS-CoV-2 either through inhalation of airborne viral particles or by touching contaminated surfaces. Structural and functional studies have shown that a single RBD of the SARS-CoV-2 homotrimer spike glycoprotein interacts with ACE2, which serves as its receptor 1,2. Binding of spike (S) protein to ACE2 and subsequent cleavage by the host protease transmembrane serine protease 2 (TMPRSS2) results in cell and virus membrane fusion and cell entry 1. Blocking of the ACE2 receptor by specific antibodies prevents viral entry 1,3-5. In vitro binding measurements have shown that SARS-CoV-2 S protein binds ACE2 with an affinity of around 10 nM, which is about tenfold tighter than the binding of the SARS-CoV S protein 2,4,6. It has been suggested that this is, at least partially, responsible for the higher infectivity of SARS-CoV-2 7. Recently, three major SARS-CoV2 variants of concern have emerged and mutations in the RBD of the spike proteins of these variants have further strengthened this hypothesis. Deep-mutational scanning of the RBD domain showed that the N501Y mutation in the Alpha variant to enhances binding to ACE2 7. The Beta variant has three altered residues in the ACE2-binding site (K417N, E484K and N501Y), and has spread extremely rapidly, becoming the dominant lineage in the Eastern Cape and Western Cape Provinces within weeks 8. The Gamma variant, with independent K417T, E484K and N501Y mutations, similar to the B.1.351 variant is spreading rapidly from the Amazon region 9. Another S mutation associated with

Dates and versions

pasteur-03321160 , version 1 (17-08-2021)

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Jiří Zahradník, Shir Marciano, Maya Shemesh, Eyal Zoler, Daniel Harari, et al.. SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution.. Nature Microbiology, 2021, ⟨10.1038/s41564-021-00954-4⟩. ⟨pasteur-03321160⟩
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