Antiviral researchAug 30, 2025

A designed peptide combining ACE2 and HR2 parts shows strong and wide-ranging activity against SARS-CoV-2 variants

Updated Jan 2, 2026

Abstract

A3M6L35HR2 (FL) demonstrated inhibitory potency against SARS-CoV-2 variants with IC values ranging from 1.7 to 16.2 nM.

A3M6L35HR2 (FL) showed 2- to 29-fold enhanced activity compared to its predecessor A1L35HR2.
The peptide exhibits 70% α-helicity and a strong binding affinity of K = 0.03 nM with the viral HR1 domain.
It effectively suppresses spike-mediated membrane fusion at nanomolar concentrations.
The combination of A3M6L35HR2 (FL) with RBD-targeting protein T-ACE2 resulted in an antagonistic effect due to competitive binding.

Simplified

The persistent circulation of SARS-CoV-2 and limited efficacy of current vaccines in preventing viral transmission underscore the critical need for broad-spectrum antivirals. Here, we report a novel engineering strategy to develop A3M6L35HR2 (FL), a cholesterol-free recombinant peptide derived from our previously reported A1L35HR2, by incorporating an optimized angiotensin-converting enzyme 2 (ACE2)-mimetic peptide A3M6 with six residue mutations. A3M6L35HR2 (FL) exhibited superior inhibitory potency against diverse SARS-CoV-2 variants with ICfrom 1.7 to 16.2 nM, including antigenically distinct Omicron sublineages, achieving 2- to 29-fold enhanced activity compared to A1L35HR2. A3M6L35HR2 (FL) exhibits a higher α-helicity (70 %) and stronger binding affinity (K = 0.03 nM) with the viral HR1 domain, thereby effectively suppressing spike-mediated membrane fusion at nanomolar concentrations. Combining A3M6L35HR2 (FL) with RBD-targeting protein T-ACE2 exhibited antagonistic effect, attributed to competitive RBD binding by both agents. These findings establish A3M6L35HR2 (FL) as a promising antiviral candidate against current and emerging SARS-CoV-2 variants. 50D

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Competing interests

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. W.B., T.Z., Y.H., Y.C, J.L., and H.Y. have a provisional patent application. The authors declare no competing interests.

PubMed

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A designed peptide combining ACE2 and HR2 parts shows strong and wide-ranging activity against SARS-CoV-2 variants

Abstract

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Funding

Competing interests

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