Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Nat Chem. 2018 Jul;10(7):715-723. doi: 10.1038/s41557-018-0042-7. Epub 2018 Apr 30.
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, >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 in plasma of >3 days), making double-bridged peptides potentially amenable to topical or oral delivery.
成功的筛选活动依赖于大量结构多样的化合物集合。在大环筛选中，分子支架的变化对于结构多样性很重要，但迄今为止，在大型组合库中对此方面进行多样化具有挑战性。在这里，我们报告了使用两个化学桥连接的肽的环化，从而可以快速获得易于合成、筛选和解码的库中的数千种不同的大环支架。该策略在噬菌体编码文库中的应用允许针对血浆激肽释放酶筛选前所未有的大环结构多样性，这在肿胀性疾病遗传性血管性水肿中很重要。尽管这些文库中的分子质量较小（约 1200Da），但仍具有显著的结合特性（亚纳摩尔 K，>1000 倍的选择性）。该策略的特征是交错桥接格式，提供了较高的蛋白水解稳定性（在血浆中 t >3 天），使得双桥接肽具有潜在的局部或口服递送能力。
