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Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor <jats:bold>CV122<\/jats:bold> is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)\u2010induced sepsis mouse models are evaluated. It is found that <jats:bold>CV122<\/jats:bold> potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, <jats:bold>CV122<\/jats:bold> significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis\u2010induced death. Mechanistically, <jats:bold>CV122<\/jats:bold> inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that <jats:bold>CV122<\/jats:bold> provides effective protection from organ damage and death caused by Crimean\u2010Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that <jats:bold>CV122<\/jats:bold> is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.<\/jats:p>","DOI":"10.1002\/advs.202403337","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T14:34:19Z","timestamp":1716993259000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm"],"prefix":"10.1002","volume":"11","author":[{"given":"Danyang","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiutong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianwei","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haomiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road, Haihe Education Park Tianjin 300350 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Health and Life Sciences Qingdao Central Hospital University 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