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Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2.

Ross C Larue1, Enming Xing2, Adam D Kenney3

  • 1Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, Ohio 43210, United States.

Bioconjugate Chemistry
|December 28, 2020
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Summary

Researchers designed ACE2-derived peptides to block SARS-CoV-2 entry. These peptides effectively inhibited SARS-CoV-2 and other coronaviruses, showing promise for developing new COVID-19 peptide therapies.

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Area of Science:

  • Virology
  • Drug Discovery
  • Biochemistry

Background:

  • Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 causes COVID-19, a disease with high morbidity and mortality.
  • Effective antiviral therapies are urgently needed due to the lack of approved drugs or vaccines.
  • Targeting essential viral proteins, like the Spike glycoprotein, is a key strategy for controlling viral replication.

Purpose of the Study:

  • To design and evaluate ACE2-derived peptides as potential inhibitors of SARS-CoV-2 entry.
  • To investigate the efficacy of these peptides against SARS-CoV-2 and related coronaviruses.
  • To identify key structural motifs involved in the inhibition of viral entry.

Main Methods:

  • Rational design of ACE2-derived peptides based on Spike RBD-ACE2 binding interfaces.
  • Testing peptide inhibition using SARS-CoV-2 and SARS-CoV Spike-pseudotyped viruses.
  • Affinity precipitation assays to confirm peptide binding to Spike RBD.
  • Infection experiments with genuine SARS-CoV-2 and a common cold coronavirus.
  • Molecular modeling to identify critical amino acid residues.

Main Results:

  • A subset of designed peptides inhibited Spike-mediated infection with IC50 values in the low millimolar range.
  • Two peptides demonstrated binding to Spike RBD and inhibited infection with authentic SARS-CoV-2.
  • These peptides also inhibited the replication of a common cold coronavirus utilizing ACE2 for entry.
  • A 6-amino-acid motif (Glu37-Gln42) in ACE2 was identified as important for SARS-CoV-2 inhibition.

Conclusions:

  • ACE2-derived peptides can effectively inhibit SARS-CoV-2 entry and replication.
  • This study demonstrates the feasibility of developing peptide-based inhibitors for COVID-19 treatment.
  • Findings support the development of engineered peptides and peptidomimetics for therapeutic applications against SARS-CoV-2.