Halland Nis, Brönstrup Mark, Czech Jörg, Czechtizky Werngard, Evers Andreas, Follmann Markus, Kohlmann Markus, Schiell Matthias, Kurz Michael, Schreuder Herman A, Kallus Christopher
‡Helmholtz Institute for Infection Research, Inhoffenstraße 7, D-38124 Braunschweig, Germany.
§Bayer Healthcare, Aprather Weg 18A, D-42113 Wuppertal, Germany.
J Med Chem. 2015 Jun 11;58(11):4839-44. doi: 10.1021/jm501840b. Epub 2015 May 20.
Anabaenopeptins isolated from cyanobacteria were identified as inhibitors of carboxypeptidase TAFIa. Cocrystal structures of these macrocyclic natural product inhibitors in a modified porcine carboxypeptidase B revealed their binding mode and provided the basis for the rational design of small molecule inhibitors with a previously unknown central urea motif. Optimization based on these design concepts allowed for a rapid evaluation of the SAR and delivered potent small molecule inhibitors of TAFIa with a promising overall profile.
从蓝藻中分离出的鱼腥藻肽被鉴定为羧肽酶TAFIa的抑制剂。这些大环天然产物抑制剂与修饰的猪羧肽酶B的共晶体结构揭示了它们的结合模式，并为合理设计具有前所未知的中心尿素基序的小分子抑制剂提供了基础。基于这些设计理念进行优化，能够快速评估构效关系，并得到具有良好整体特性的强效TAFIa小分子抑制剂。
