Inhibition of ACE2-Spike Interaction by an ACE2 Binder Suppresses SARS-CoV-2 Entry

Angew Chem Int Ed Engl. 2022 Mar 7;61(11):e202115695. doi: 10.1002/anie.202115695. Epub 2022 Feb 1.

Abstract

The emergence of SARS-CoV-2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID-19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS-CoV-2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS-CoV-2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS-CoV-2 entry into host cells and prevent the development of COVID-19.

Keywords: ACE2 Inhibition; Allostery; COVID-19; PPI Inhibition; Virus Entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment*
  • Chlorocebus aethiops
  • Drug Discovery
  • Humans
  • Protein Interaction Maps / drug effects
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Vero Cells
  • Virus Internalization / drug effects*

Substances

  • Antiviral Agents
  • Small Molecule Libraries
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants