Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA.
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University College of Medicine, 700 Children's Drive, Columbus, OH 43205, USA.
J Am Chem Soc. 2013 Aug 14;135(32):11990-5. doi: 10.1021/ja405106u. Epub 2013 Aug 1.
Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well-defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-α (TNFα) identified a potent antagonist that inhibits the TNFα-TNFα receptor interaction and protects cells from TNFα-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions.
蛋白质-蛋白质相互作用代表了一类令人兴奋但具有挑战性的新型药物靶点，因为它们的大而平坦的结合位点缺乏小分子结合的明确口袋。我们在这里报告了一种在刚性小分子支架上展示的双环肽的化学合成和大规模组合文库筛选的方法。以平面均苯三甲酸为支架，所得的双环肽可有效结合蛋白质表面，如蛋白质-蛋白质相互作用的界面。针对肿瘤坏死因子-α（TNFα）的双环肽文库筛选出一种有效的拮抗剂，该拮抗剂可抑制 TNFα-TNFα 受体相互作用并保护细胞免受 TNFα 诱导的细胞死亡。这种类型的双环肽可能为抑制蛋白质-蛋白质相互作用提供了一种通用的解决方案。
