This study develops peptide inhibitors targeting SFTSV host–pathogen interactions, specifically blocking viral Gn binding to host receptors DC-SIGN and NMMHC-IIA. Using rational design and screening, peptides II-1 and II-4 exhibit potent antiviral activity, high binding affinity (KD ≈ 10⁻⁸ M), low cytotoxicity, and minimal hemolytic toxicity. Molecular dynamics confirm stable binding, offering a promising platform for SFTSV therapeutics.

Severe fever with thrombocytopenia syndrome virus (SFTSV) poses a significant threat to public health, with limited therapeutic options available. This study focuses on the rational design and screening of peptide inhibitors targeting host–pathogen interactions, specifically between the viral Gn glycoprotein and key host cell receptors, DC-SIGN and NMMHC-IIA. By employing molecular dynamics simulations, alanine scanning, and peptide docking techniques, peptides were designed to disrupt these protein–protein interactions. Among the synthesized candidates, peptides II-1 and II-4 demonstrate potent inhibitory activity against SFTSV infection, with reduced TCID₅₀ values in cellular assays and displayed exceptional affinity (KD = 7.381 × 10⁻⁸ M, 1.439 × 10⁻⁸ M), These peptides also exhibit low cytotoxicity and hemolytic toxicity, highlighting their safety profile. Molecular dynamics simulations confirm strong binding affinities for these peptides, underpinned by stable hydrogen bonding interactions. This research provides a promising platform for developing peptide-based therapeutics targeting SFTSV, paving the way for further preclinical evaluation and clinical applications.