Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema. These libraries yielded inhibitors with remarkable binding properties (subnanomolar K_i, >1,000-fold selectivity) despite the small molecular mass (~1,200 Da). An interlaced bridge format characteristic of this strategy provided high proteolytic stability (t_1/2 in plasma of >3 days), making double-bridged peptides potentially amenable to topical or oral delivery.

成功的筛选活动取决于大量和结构多样的化合物集合。在大环筛选中，分子支架的变异对于结构多样性很重要，但到目前为止，在大型组合文库中使这一方面多样化一直是挑战。在这里，我们报道了具有两个化学桥的肽环化反应，可快速访问易于合成，筛选和解码的文库中数千种不同的大环骨架。该策略在噬菌体编码文库中的应用允许筛选针对血浆激肽释放酶的大环空前的结构多样性，这在肿胀性疾病遗传性血管性水肿中很重要。这些文库产生了具有显着结合特性的抑制剂（亚纳摩尔级K _i，尽管分子量较小（〜1,200 Da），但选择性> 1,000倍）。这种策略的隔行桥格式特性提供了高蛋白水解稳定性（血浆中t _1/2 > 3天，t _1/2），使得双桥肽可能适合局部或口服给药。