Uhlíková T, Konvalinka J, Pichová I, Soucek M, Kräusslich H G, Vondrásek J
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Biochem Biophys Res Commun. 1996 May 6;222(1):38-43. doi: 10.1006/bbrc.1996.0694.
HIV-1 proteinase represents a promising target for antiviral chemotherapy. We have designed, synthesized, and tested modular inhibitors combining an active-site inhibitor tethered to a structure targeted to the dimerization domain of the enzyme. At pH 5 the parent active site inhibitor, the equimolar mixture of active site and dimerization inhibitors, and the best compound from our series of modular inhibitors show the same inhibition activity. At neutral pH, however, the combination of the dimerization and active-site inhibitors shows a synergistic effect. Moreover, the modular inhibitor has an IC50 value 5x lower than the parent active site inhibitor and 2x lower than the equimolar mixture of the two parent inhibitors. The Lineweaver-Burk plot for modular inhibitors corresponds to a pattern for mixed type inhibition.
HIV-1蛋白酶是抗病毒化疗的一个有前景的靶点。我们设计、合成并测试了模块化抑制剂，其将活性位点抑制剂与靶向该酶二聚化结构域的结构相连。在pH 5时，母体活性位点抑制剂、活性位点和二聚化抑制剂的等摩尔混合物以及我们系列模块化抑制剂中的最佳化合物表现出相同的抑制活性。然而，在中性pH下，二聚化抑制剂和活性位点抑制剂的组合显示出协同效应。此外，模块化抑制剂的IC50值比母体活性位点抑制剂低5倍，比两种母体抑制剂的等摩尔混合物低2倍。模块化抑制剂的Lineweaver-Burk图对应于混合型抑制模式。
