Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4860-4. doi: 10.1016/j.bmcl.2011.06.033. Epub 2011 Jun 21.
A series of substrate analogue inhibitors of the serine protease HAT, containing a 4-amidinobenzylamide moiety as the P1 residue, was prepared. The most potent compounds possess a basic amino acid in the d-configuration as P3 residue. Whereas inhibitor 4 (K(i) 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, K(i) 15 nM) with improved selectivity for HAT in comparison to the coagulation proteases thrombin and factor Xa or the fibrinolytic plasmin. Selected inhibitors were able to suppress influenza virus replication in a HAT-expressing MDCK cell model.
我们制备了一系列丝氨酸蛋白酶 HAT 的类似物抑制剂，这些抑制剂都含有 4-脒基苯甲酰胺作为 P1 残基。最有效的化合物在 P3 位含有 D-构型的碱性氨基酸。而抑制剂 4（K(i) 为 13 nM），其中脯氨酸作为 P2 残基，完全没有选择性，而掺入正缬氨酸则导致对 HAT 具有更高选择性的有效抑制剂（15，K(i) 为 15 nM），与凝血蛋白酶凝血酶和因子 Xa 或纤维蛋白溶解酶纤溶酶相比。选择的抑制剂能够抑制在表达 HAT 的 MDCK 细胞模型中的流感病毒复制。
