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Repurposing of rilpivirine for preventing platelet ß3 integrin-dependent thrombosis by targeting c-Src active autophosphorylation.
Liu, Kui; Hao, Zhen; Zheng, Hao; Wang, Haojie; Zhang, Luying; Yan, Minghui; Tuerhong, Reyisha; Zhou, Yuling; Wang, Yan; Pang, Tao; Shi, Lei.
Afiliação
  • Liu K; Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, 2999 Jinshan Road, Xiamen 361000, China; State Key Laboratory of Natural Medicines, New Drug Screening Center, Key Laboratory of Drug Quality Control and Pharm
  • Hao Z; Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, 2999 Jinshan Road, Xiamen 361000, China; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, C
  • Zheng H; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, China.
  • Wang H; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Zhang L; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, China.
  • Yan M; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, China.
  • Tuerhong R; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, China.
  • Zhou Y; Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, 2999 Jinshan Road, Xiamen 361000, China.
  • Wang Y; Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, 2999 Jinshan Road, Xiamen 361000, China. Electronic address: wy@medmail.com.cn.
  • Pang T; State Key Laboratory of Natural Medicines, New Drug Screening Center, Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China. Electronic address: tpang@cpu.edu.cn.
  • Shi L; Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, 2999 Jinshan Road, Xiamen 361000, China; College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section, South Lv shun Road, Dalian 116044, C
Thromb Res ; 229: 53-68, 2023 09.
Article em En | MEDLINE | ID: mdl-37413892
ABSTRACT

BACKGROUND:

HIV-infected individuals are known to be at higher risk for thrombotic cardiovascular disease (CVD), which may also be differentially affected by components of anti-HIV drugs. To identify the effects of a series of FDA-approved anti-HIV drugs on platelet aggregation in humans, focusing on the novel pharmacological effects of rilpivirine (RPV), a reverse transcriptase inhibitor, on platelet function both in vitro and in vivo and the mechanisms involved. METHODS AND

RESULTS:

In vitro studies showed that RPV was the only anti-HIV reagent that consistently and efficiently inhibited aggregation elicited by different agonists, exocytosis, morphological extension on fibrinogen, and clot retraction. Treatment of mice with RPV significantly prevented thrombus formation in FeCl3-injured mesenteric vessels, postcava with stenosis surgery, and ADP -induced pulmonary embolism models without defects in platelet viability, tail bleeding, and coagulation activities. RPV also improved cardiac performance in mice with post-ischemic reperfusion. A mechanistic study revealed that RPV preferentially attenuated fibrinogen-stimulated Tyr773 phosphorylation of ß3-integrin by inhibiting Tyr419 autophosphorylation of c-Src. Molecular docking and surface plasmon resonance analyses showed that RPV can bind directly to c-Src. Further mutational analysis showed that the Phe427 residue of c-Src is critical for RPV interaction, suggesting a novel interaction site for targeting c-Src to block ß3-integrin outside-in signaling.

CONCLUSION:

These results demonstrated that RPV was able to prevent the progression of thrombotic CVDs by interrupting ß3-integrin-mediated outside-in signaling via inhibiting c-Src activation without hemorrhagic side effects, highlighting RPV as a promising reagent for the prevention and therapy of thrombotic CVDs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Fármacos Anti-HIV Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Fármacos Anti-HIV Idioma: En Ano de publicação: 2023 Tipo de documento: Article