A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm

Wang, Danyang1,2; Wang, Kaixuan1,2; Liu, Qiutong1,2; Liu, Mingyang1,2; Zhang, Guoqiang1,2; Feng, Ke1,2; Wang, Kun1,2; Ding, Xianwei1,2; Zhu, Haomiao1,2; Yang, Song3; Liu, Yonghui1,2; Li, Tiehai4; Gong, Peng5; Wang, Manli5; Wang, Peng George6; Jin, Hongzhen3; Zhao, Wei1,2; Yu, Fan3

2024-05-01

10.1002/advs.202403337

ADVANCED SCIENCE   影响因子和分区

2198-3844

["Sepsis is an infection-triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. 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 CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)-induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis-induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean-Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.","Sepsis currently has no specific clinical treatment. The main cause of multi-organ failure and death in sepsis is increased vascular permeability due to endothelial damage. A drug targeting Heparanase through screening is developed. The drug significantly improved survival rates in sepsis mouse models from 0% to 80%, making it a promising candidate for sepsis. image"]

cytokine storm glycocalyx heparanase sepsis

SCI ; EI

英语

其他

Natural Science Foundation of Tianjin, China[21JCZDJC00200] ; null[22377060] ; null[22077068]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:001234252500001

WILEY

Web of Science

1.Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Key Lab Mol Drug Res Tianjin, Tongyan Rd,Haihe Educ Pk, Tianjin 300350, Peoples R China
2.Nankai Univ, KLMDASR Tianjin, Tongyan Rd, Haihe Educ Pk, Tianjin 300350, Peoples R China
3.Univ Hlth & Rehabil Sci, Qingdao Cent Hosp, Sch Hlth & Life Sci, Qingdao 266113, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Carbohydrate Based Drug Res Ctr, Shanghai 201203, Peoples R China
5.Wuhan Inst Virol, Chinese Acad Sci, State Key Lab Virol, Wuhan 430071, Peoples R China
6.Southern Univ Sci & Technol, Sch Med, Shenzhen 518000, Peoples R China

Wang, Danyang,Wang, Kaixuan,Liu, Qiutong,et al. A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm[J]. ADVANCED SCIENCE,2024.

Wang, Danyang.,Wang, Kaixuan.,Liu, Qiutong.,Liu, Mingyang.,Zhang, Guoqiang.,...&Yu, Fan.(2024).A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm.ADVANCED SCIENCE.

Wang, Danyang,et al."A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm".ADVANCED SCIENCE (2024).