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

Full Text

Full text is available at the source.

View Full Text ↗

Featured in

Long CovidIssue #1

Depression linked to 28% lower COVID vaccination rates and 21% higher long COVID risk

↗

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

Abstract

Full Text

Featured in

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the long covid brief