Perni Robert B, Chandorkar Gurudatt, Cottrell Kevin M, Gates Cynthia A, Lin Chao, Lin Kai, Luong Yu-Ping, Maxwell John P, Murcko Mark A, Pitlik Janos, Rao Govinda, Schairer Wayne C, Van Drie John, Wei Yunyi
Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2007 Jun 15;17(12):3406-11. doi: 10.1016/j.bmcl.2007.03.090. Epub 2007 Apr 3.
Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.
基于可逆四肽的化合物已被证明能有效抑制丙型肝炎病毒NS3.4A蛋白酶。在Huh-7细胞中对病毒复制子RNA产生的抑制作用也已得到证实。我们在此表明，在基于四肽的抑制剂的P4封端基团上引入氢键供体可提高对NS3.4A蛋白酶的结合效力。封端基团对这些抑制剂的药代动力学特征也有显著影响。
