Wiedemeyer Simon J A, Wu Guojie, Pham T L Phuong, Lang-Henkel Heike, Perez Urzua Benjamin, Whisstock James C, Law Ruby H P, Steinmetzer Torsten
Department of Pharmacy Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
Biomedicine Discovery Institute Department of Biochemistry and Molecular Biology, Monash University, Melbourne, 3800, Australia.
ChemMedChem. 2023 Mar 14;18(6):e202200632. doi: 10.1002/cmdc.202200632. Epub 2023 Feb 7.
Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with K values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.
合成了两组具有C端苄胺基团的大环纤溶酶抑制剂。对先前描述的一种抑制剂的N端苯磺酰基进行取代，得到了两种抑制常数低于纳摩尔级的类似物。这两种化合物对所有其他测试的类胰蛋白酶丝氨酸蛋白酶都具有高选择性。此外，采用了一种新方法来选择性引入不对称连接片段。其中两种化合物抑制纤溶酶的K值接近2 nM。首次测定了这些大环抑制剂与Ser195Ala微纤溶酶突变体复合物的四个晶体结构。抑制剂的大环核心片段与纤溶酶的开放活性位点结合，没有任何空间位阻。这种结合模式与其他含有空间要求较高的99发夹环的类胰蛋白酶丝氨酸蛋白酶不兼容。实验获得的晶体结构解释了如先前假设的这种抑制剂类型的优异选择性。
