Babinska A, Clement C C, Swiatkowska M, Szymanski J, Shon A, Ehrlich Y H, Kornecki E, Salifu M O
Division of Nephrology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, 11203; Department of Cell Biology and Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, 11203.
Biopolymers. 2014 Jul;102(4):322-34. doi: 10.1002/bip.22503.
Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D-Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events.
基于F11受体分子（F11R，又名JAM-A/连接黏附分子-A）的氨基酸序列，设计、制备并研究了具有增强抗蛋白水解能力的肽，作为抗动脉粥样硬化和抗血栓治疗药物开发的潜在候选物。已确定F11R N端的一个序列以及该蛋白第一个免疫球蛋白环中的另一个序列，共同构成一个空间活性位点，该位点在表达F11R分子的细胞之间的F11R依赖性黏附中起作用。利用计算机模拟两条多肽链之间的复合物，其中序列位于活性位点，以生成旨在抑制表面F11R分子之间同源相互作用的候选肽。在选择性位点用D-精氨酸和D-赖氨酸对两种主要的F11R肽进行修饰，以获得更高的体内抗蛋白水解稳定性。通过分子对接实验，我们测试了两种选定的D-精氨酸和D-赖氨酸修饰的F11R肽的不同构象状态以及假定的结合亲和力与提议的结合口袋之间的关系。详细报道了F11R肽2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2对抗体诱导的血小板聚集以及血小板与细胞因子炎症内皮细胞黏附的抑制作用，结果指出F11R肽在预防和治疗动脉粥样硬化斑块及相关血栓形成事件方面具有显著的潜在应用价值。
