A rational design strategy and validation for protease-resistant fusion-inhibitor antiviral peptides

HR2-domain fusion-inhibitor peptides with the SARS-CoV-2 spike wildtype sequence are efficiently cleaved by TMPRSS2, and a protease-resistant HR2-NHN variant binds HR1 with potent activity.

• Why it matters: Peptide antivirals are limited by poor in vivo stability, and TMPRSS2 cleavage in the SARS-CoV-2 fusion pathway undermines HR2-based fusion inhibition.
• What they did: The team mapped TMPRSS2 cleavage sites and designed three protease-resistant peptides using ranking from deep mutational scanning and natural occurrence, then tested them in cell-cell fusion assays and solved a cryo-EM structure for HR2-NHN.
• The result: The three candidates inhibited fusion in cells, and the top screened peptide showed significantly improved efficacy versus the wildtype when dosed at different times before infection in authentic virus-cell infection and mouse assays.

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