Krawczyk Mariusz, Wasowska-Lukawska Malgorzata, Oszczapowicz Irena, Boguszewska-Chachulska Anna M
Institute of Biochemistry and Biophysics PAS, Pawinskiego 5a, 02-106 Warsaw, Poland.
Biol Chem. 2009 Apr;390(4):351-60. doi: 10.1515/BC.2009.040.
Hepatitis C virus (HCV) infections represent one of the major and still unresolved health problems because current therapy is effective in only 50-80% of cases, depending on viral genotype. A large group of amidinoanthracyclines, with decreased acute toxicity and cardiotoxicity compared to the parent antibiotics, was tested in a high-throughput fluorometric HCV helicase assay. Here, we report the selection of more than 50 potent inhibitors of helicase activity that inhibit the enzyme with IC(50) values in the range of 0.03- 10 mum; four of these compounds are the most potent inhibitors of helicase activity described in the literature. The activity of these inhibitors is highly dependent on their chemical structure, mainly on the substituent at the amidino carbon atom and on the orientation of the hydroxyl group at the 4 inch position of the daunosamine moiety. The most effective compounds act not solely via intercalation into the double-stranded DNA substrate, but also compete with the enzyme for access to the substrate, impeding formation of the active helicase complex. Selected amidinoanthracyclines were tested in the subgenomic HCV replicon system. These experiments confirmed the antiviral activity of two selected inhibitors (EC(50) values below 0.2 mum with selectivity indices of 19 and 33) and proved that they may be considered as potential anti-HCV drugs.
丙型肝炎病毒（HCV）感染是主要且尚未解决的健康问题之一，因为目前的治疗方法仅在50%-80%的病例中有效，这取决于病毒基因型。与母体抗生素相比，一大类急性毒性和心脏毒性降低的脒基蒽环类化合物在高通量荧光HCV解旋酶测定中进行了测试。在此，我们报告了筛选出50多种有效的解旋酶活性抑制剂，这些抑制剂对该酶的抑制IC(50)值在0.03-10 μM范围内；其中四种化合物是文献中描述的最有效的解旋酶活性抑制剂。这些抑制剂的活性高度依赖于它们的化学结构，主要取决于脒基碳原子上的取代基以及柔红糖胺部分4位羟基的取向。最有效的化合物不仅通过插入双链DNA底物起作用，还与酶竞争接近底物的机会，从而阻碍活性解旋酶复合物的形成。在亚基因组HCV复制子系统中对选定的脒基蒽环类化合物进行了测试。这些实验证实了两种选定抑制剂的抗病毒活性（EC(50)值低于0.2 μM，选择性指数分别为19和33），并证明它们可被视为潜在的抗HCV药物。
