2. Academic Validation
  3. A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism

A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism

  • Bioorg Med Chem Lett. 2016 Oct 1;26(19):4631-4636. doi: 10.1016/j.bmcl.2016.08.061.
Jianhui Wu 1,  Ming Zhao 2,  Yuji Wang 1,  Yaonan Wang 1,  Haimei Zhu 1,  Shurui Zhao 1,  Shiqi Peng 3
Affiliations

Affiliations

  • 1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
  • 2 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: mingzhao@bjmu.edu.cn.
  • 3 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China. Electronic address: sqpeng@bjmu.edu.cn.
PMID: 27575475 DOI: 10.1016/j.bmcl.2016.08.061
Abstract

By docking 126 derivatives of β-carboline-3-carboxylic acid, tetrahydro-β-carboline-3-carboxylic acid and indoloquinolizine into the active pocket of P-selectin (2-(3-(hydroxymethyl)-9H-pyrido[3,4-b]indol-1-yl)ethyl)-l-phenylalanine (HMCEF) was assigned a novel inhibitor. ELISA and flow cytometry experiments showed that HMCEF effectively down-regulated P-selectin expression and supported the rationality of the computer assistant screening, while UV spectrum experiments demonstrated that HMCEF directly bound to P-selectin. In vivo HMCEF dose dependently inhibited the rats and mice to form thrombus and had a minimal effective dose of 20nmol/kg, dose dependently inhibited inflammatory response of mice and had a minimal effective dose of 20nmol/kg. The decrease of serum TNFα and IL-8 of the treated mice was proposed to be the action mechanism of HMCEF inhibiting thrombosis and inflammation. All data imply that HMCEF is a novel lead of P-selectin Inhibitor.

Keywords

Anti-inflammation; Anti-thrombosis; Inhibitor; P-selectin; β-Carboline.

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