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An enhanced broad-spectrum peptide inhibits Omicron variants in vivo

Wenwen Bi1, Kaiming Tang2, Guilin Chen3

  • 1Research Center for Industries of the Future and Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, Zhejiang, China; Frontier Biotechnology Laboratory, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310030, China.

Cell Reports. Medicine
|February 10, 2024
PubMed

Insights

A novel cholesterol-modified peptide, A1L35HR2m-Chol, demonstrates potent broad-spectrum antiviral activity against SARS-CoV-2 variants and other coronaviruses. This inhibitor shows promise for respiratory tract infections with effective in vivo prophylactic and therapeutic effects.

Area of Science:

  • Virology
  • Drug Discovery
  • Biochemistry

Background:

  • Emergence of SARS-CoV-2 variants of concern (VOCs) challenges existing vaccines and therapeutics.
  • Viral immune evasion necessitates development of broad-spectrum antiviral inhibitors.

Purpose of the Study:

  • To develop potent and broad-spectrum inhibitors against coronaviruses, including SARS-CoV-2 VOCs.
  • To evaluate the efficacy of a novel peptide inhibitor, A1L35HR2m-Chol, against SARS-CoV-2 and other coronaviruses.

Main Methods:

  • Generation of A1L35HR2m by linking an ACE2-derived peptide to a viral HR2-derived peptide via a flexible linker.
  • Cholesterol modification of A1L35HR2m to create A1L35HR2m-Chol.
  • In vitro assays using pseudoviruses and authentic SARS-CoV-2 variants (Omicron BA.2.12.1, BA.5, EG.5.1).
  • In vivo studies involving intranasal administration to K18-hACE2 transgenic mice.

Main Results:

  • A1L35HR2m-Chol exhibited enhanced inhibitory activity against SARS-CoV-2, VOCs, SARS-CoV, and MERS-CoV pseudoviruses (IC50: 0.16–5.53 nM).
  • The inhibitor effectively blocked spike-protein-mediated cell-cell fusion and replication of authentic Omicron variants.
  • A1L35HR2m-Chol showed wide distribution in respiratory tissues and a long in vivo half-life (>10 h).
  • Intranasal A1L35HR2m-Chol provided potent prophylactic and therapeutic protection against Omicron BA.5 and EG.5.1 infection in mice.

Conclusions:

  • A1L35HR2m-Chol is a potent broad-spectrum antiviral agent against SARS-CoV-2 and other coronaviruses.
  • The inhibitor demonstrates favorable pharmacokinetic properties and significant therapeutic potential for respiratory coronavirus infections.
Keywords:
ACE2 peptideHR2 peptideSARS-CoV-2cholesterol modificationlipopeptidepan-coronavirus fusion inhibitorsynergistic effectvariants of concern

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