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This study focuses on the rational design and screening of peptide inhibitors targeting host\u2013pathogen interactions, specifically between the viral Gn glycoprotein and key host cell receptors, DC\u2010SIGN and NMMHC\u2010IIA. By employing molecular dynamics simulations, alanine scanning, and peptide docking techniques, peptides were designed to disrupt these protein\u2013protein interactions. Among the synthesized candidates, peptides <jats:bold>II\u20101<\/jats:bold> and <jats:bold>II\u20104<\/jats:bold> demonstrate potent inhibitory activity against SFTSV infection, with reduced TCID<jats:sub>50<\/jats:sub> values in cellular assays and displayed exceptional affinity (KD\u2009=\u20097.381\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>\u2009M, 1.439\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>\u2009M), 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\u2010based therapeutics targeting SFTSV, paving the way for further preclinical evaluation and clinical applications.<\/jats:p>","DOI":"10.1002\/cbic.202500296","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T10:34:03Z","timestamp":1749551643000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rational Design and Bioactive Screening of Peptide Inhibitors Targeting Host\u2013Pathogen Interactions in Severe Fever with Thrombocytopenia Syndrome Virus"],"prefix":"10.1002","volume":"26","author":[{"given":"Lixin","family":"Yang","sequence":"first","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing 211198 P. R. 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