Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis
文献类型：期刊论文
| 作者 | Mao, Jianhua1; Zhu, Kongkai2; Long, Zhangbiao1; Zhang, Huimin2,3; Xiao, Bing1; Xi, Wenda4; Wang, Yun1; Huang, Jiansong1; Liu, Jingqiu2; Shi, Xiaofeng1 |
| 刊名 | ADVANCED SCIENCE
 |
| 出版日期 | 2022-03 |
| 卷号 | 9期号:7页码:2103228 |
| 关键词 | antithrombotic target bleeding risk E97A knock-in mice small molecule beta 3/Src interaction |
| DOI | 10.1002/advs.202103228 |
| 文献子类 | Article |
| 英文摘要 | Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin alpha IIb beta 3 outside-in signaling by separating the beta 3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin beta 3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with beta 3. DCDBS84, a small molecule resulting from structure-based virtual screening, is structurally validated to be directed toward the projected target. It specifically disrupts beta 3/Src interaction without affecting canonical PXXP binding and thus inhibits the outside-in signaling-regulated platelet functions. Treatment of mice with DCDBS84 causes a profound inhibition of thrombosis, equivalent to that induced by extremely high doses of alpha IIb beta 3 antagonist, but does not compromise primary hemostasis. Specific targets are revealed for a preferential inhibition of thrombosis that may lead to new classes of potent antithrombotics without hemorrhagic side effects. |
| WOS关键词 | ELEVATION MYOCARDIAL-INFARCTION ; TYROSINE KINASE INHIBITORS ; INTEGRIN CYTOPLASMIC TAIL ; ACCURATE DOCKING ; ACTIVATION ; PROTEIN ; ORGANIZATION ; DISCOVERY ; INSIGHTS ; COMPLEX |
| WOS研究方向 | Chemistry ; Science & Technology - Other Topics ; Materials Science |
| 语种 | 英语 |
| 出版者 | WILEY |
| WOS记录号 | WOS:000741829800001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309363]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Luo, Cheng; Xi, Xiaodong |
| 作者单位 | 1.Shanghai Jiao Tong Univ, State Key Lab Med Genom, Collaborat Innovat Ctr Hematol, Shanghai Inst Hematol,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China; 2.Chinese Acad Sci, Univ Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res,Shanghai Ins, Shanghai 201203, Peoples R China; 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 4.Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Shanghai Inst Hypertens, Shanghai 200025, Peoples R China; 5.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Mao, Jianhua,Zhu, Kongkai,Long, Zhangbiao,et al. Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis[J]. ADVANCED SCIENCE,2022,9(7):2103228. |
| APA | Mao, Jianhua.,Zhu, Kongkai.,Long, Zhangbiao.,Zhang, Huimin.,Xiao, Bing.,...&Xi, Xiaodong.(2022).Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis.ADVANCED SCIENCE,9(7),2103228. |
| MLA | Mao, Jianhua,et al."Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis".ADVANCED SCIENCE 9.7(2022):2103228. |
入库方式： OAI收割
来源：上海药物研究所
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