HLA-C–derived peptide MH-1 as an early-stage intervention against SARS-CoV-2 infection

TL;DR

A small peptide called MH-1 can block SARS-CoV-2 from infecting cells and may serve as an early treatment or prevention strategy.

Contribution

MH-1 is a novel MHC class I-derived peptide that inhibits SARS-CoV-2 infection at an early stage.

Findings

MH-1 disrupts the interaction between the SARS-CoV-2 spike protein and ACE2 receptors.

MH-1 reduces viral load and inflammation in the lungs of infected mice.

MH-1 is effective against SARS-CoV-2 variants and in cells with low ACE2 and TMPRSS2.

Abstract

Emerging evidence suggests that preventing SARS-CoV-2 from entering and infecting host cells represents an effective strategy to limit viral infection, particularly in the context of its ongoing evolution. In this study, a small peptide fragment derived from major histocompatibility complex class I (MHC class I), designated MH-1, was investigated for its ability to interfere with the early stages of SARS-CoV-2 infection.

Molecular docking was used to characterize the interaction between MH-1 and the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. The inhibitory effect of MH-1 on S protein–ACE2 binding was further evaluated using an ACE2-functionalized electrochemical impedance spectroscopy (EIS) biosensing platform. Antiviral efficacy was assessed using SARS-CoV-2 S-pseudotyped lentiviruses and SARS-CoV-2 variants in different human cells. In vivo inhibitory efficacy of MH-1 was assessed in the K18-hACE2 mouse model, followed by lung viral load measurement and histopathological assessment.

MH-1 peptide interacted with the S-RBD and disrupted S protein-ACE2 binding. MH-1 effectively reduced SARS-CoV-2 infection in cells that expressed different levels of ACE2 and TMPRSS2. Furthermore, MH-1 decreased the infection of SARS-CoV-2 in T lymphocytes that highly express HLA-C but have low levels of ACE2 and TMPRSS2. In animal studies, MH-1 reduced the viral load in the lungs of K18-hACE2 mice and reduced the infiltration of immune cells, including macrophages and T cells, into the lungs. Levels of lung damage and inflammatory cytokines were also reduced by MH-1 and restored to normal.

These findings identify MH-1 as a promising prophylactic or early-stage intervention that inhibits SARS-CoV-2 infection by interfering with spike-mediated infection of pulmonary and immune cells.

The online version contains supplementary material available at 10.1186/s10020-026-01434-3.

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