Clamp Peptides Potently Block SARS-CoV-2 and Influenza-A Entry in 3D Human Lung Models

The accelerating emergence and diversification of respiratory viruses pose a significant global health challenge, often outpacing the development and manufacturing of conventional antiviral drugs. Current therapeutic strategies, including antibodies and small molecules, frequently face limitations such as variant specificity, complex production, and slow development timelines. There is an urgent need for rapidly designable, broad-spectrum antiviral platforms that can effectively target conserved viral mechanisms and be deployed quickly. Peptide-based therapeutics offer a promising avenue due to their potential for high specificity, low toxicity, and synthetic reproducibility, addressing critical gaps in our pandemic preparedness.

Researchers developed 15-25-residue Clamp Peptides (CPs) using rational structure-based docking and machine-learning triage. These CPs were designed to target and grip conserved receptor-binding domains of viral surface proteins. The efficacy of these CPs was evaluated against various SARS-CoV-2 variants and Influenza-A strains in human tissue-engineered 3D lung models. Viral entry inhibition was measured as the primary endpoint, quantified by viral load reduction. Additionally, the study assessed for potential cytotoxicity and hemolysis at therapeutically relevant concentrations to ensure safety and tolerability of the peptide platform.

The designed Clamp Peptides (CPs) demonstrated potent antiviral activity by binding to conserved receptor-binding domains on viral surface proteins. This binding effectively blocked viral entry across a broad spectrum of SARS-CoV-2 variants and Influenza-A strains. In human tissue-engineered 3D lung models, CPs achieved a significant reduction in viral entry. Specifically, they inhibited viral entry by a remarkable 2-4 log10 across the tested pathogens, indicating a substantial decrease in infectivity. Importantly, these therapeutically relevant concentrations of CPs showed no detectable cytotoxicity or hemolysis, highlighting their favorable safety profile in the in-vitro models. This broad-spectrum efficacy, coupled with their variant-agnostic mechanism, positions CPs as a highly promising antiviral platform.

Clamp Peptides potently blocked viral entry across SARS-CoV-2 variants and Influenza-A strains in human tissue-engineered 3D lung models by 2-4 log10.