De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain

Ravindra Thakkar, Dilip K. Agarwal, Chathuranga B. Ranaweera, Susumu Ishiguro, Martin Conda-Sheridan, Natasha N. Gaudreault, Juergen A. Richt, Masaaki Tamura, Jeffrey Comer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Although effective vaccines have been developed against SARS-CoV-2, many regions in the world still have low rates of vaccination and new variants with mutations in the viral spike protein have reduced the effectiveness of most available vaccines and treatments. There is an urgent need for a drug to cure this disease and prevent infection. The SARS-CoV-2 virus enters the host cell through protein-protein interaction between the virus's spike protein and the host's angiotensin converting enzyme (ACE2). Using protein design software and molecular dynamics simulations, we have designed a 17-residue peptide (pep39), that binds to the spike protein receptor-binding domain (RBD) and blocks interaction of spike protein with ACE2. We have confirmed the binding activity of the designed peptide for the original spike protein and the delta variant spike protein using micro-cantilever and bio-layer interferometry (BLI) based methods. We also confirmed that pep39 strongly inhibits SARS-CoV-2 virus replication in Vero E6 cells. Taken together these data suggest that a newly designed spike protein RBD blocking peptide pep39 has a potential as a SARS-CoV-2 virus inhibitor.

Original languageEnglish (US)
Pages (from-to)1722-1733
Number of pages12
JournalRSC Medicinal Chemistry
Volume14
Issue number9
DOIs
StatePublished - Jul 31 2023

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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