化学
激肽释放酶
缓激肽
四肽
肽
寡肽
生物信息学
蛋白酵素
凝血酶
环肽
生物化学
酶
基因
受体
内科学
医学
血小板
作者
Daniel Ford,Nisharnthi M. Duggan,Sarah E. Fry,Jorge Ripoll‐Rozada,Stijn M. Agten,Wenyu Liu,Leo Corcilius,Tilman M. Hackeng,René van Oerle,Henri M.H. Spronk,Anneliese S. Ashhurst,Vishnu Mini Sasi,Joe A. Kaczmarski,Colin J. Jackson,Pedro José Barbosa Pereira,Toby Passioura,Hiroaki Suga,Richard J. Payne
标识
DOI:10.1021/acs.jmedchem.1c00651
摘要
The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway of coagulation and the kallikrein–kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa. Cyclic peptides were evaluated in vitro, and three lead compounds exhibited significant prolongation of aPTT, a reduction in thrombin generation, and an inhibition of bradykinin formation. We also describe our efforts to identify the critical residues for binding FXIIa through alanine scanning, analogue generation, and via in silico methods to predict the binding mode of our lead cyclic peptide inhibitors.
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