Wroclaw University of Technology, Faculty of Chemistry, Division of Medicinal Chemistry and Microbiology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland.
Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
Antiviral Res. 2017 Aug;144:286-298. doi: 10.1016/j.antiviral.2017.06.020. Epub 2017 Jun 30.
Herein, we describe the synthesis and application of novel phosphonic inhibitors designed to target the NS3/4A protease, which is crucial for the life cycle of hepatitis C virus. We examined the inhibitory potency of our synthesized compounds against two genotypes (1a and 1b) of NS3/4A protease and four mutant strains of HCV. The most potent inhibitors displayed k/K values of 79 850 Ms and 60 850 Ms against genotype 1a and 1b protease, respectively. Further in vitro evaluation of the most potent inhibitors revealed that vastly reduced HCV replication. Cellular toxicity, plasma stability, reactivity with selected human proteases as well the stability of inhibitor-protease complex and its intracellular availability are also discussed.
在此，我们描述了新型膦酸抑制剂的合成及其应用，这些抑制剂旨在针对丙型肝炎病毒生命周期中至关重要的 NS3/4A 蛋白酶。我们研究了我们合成的化合物对两种基因型（1a 和 1b）的 NS3/4A 蛋白酶和四种丙型肝炎病毒突变株的抑制效力。最有效的抑制剂对基因型 1a 和 1b 蛋白酶的 k/K 值分别为 79850 Ms 和 60850 Ms。对最有效的抑制剂的进一步体外评估表明，丙型肝炎病毒的复制大大减少。还讨论了细胞毒性、血浆稳定性、与选定的人类蛋白酶的反应性以及抑制剂-蛋白酶复合物的稳定性及其细胞内可用性。
