Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain; SeLiver Group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital CSIC University of Seville, Seville, Spain.
Department of Medical Biotechnologies, Siena University Hospital, Policlinico Le Scotte, Viale Bracci 16, 53100 Siena, Italy.
Bioorg Chem. 2023 Apr;133:106408. doi: 10.1016/j.bioorg.2023.106408. Epub 2023 Feb 4.
Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC 6.6 µM and 1.9 µM respectively) and DENV (IC 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases' active sites.
自 2011 年以来，已有针对不同非结构（NS）病毒蛋白（NS3、NS5A 或 NS5B 抑制剂）的直接作用抗病毒（DAA）药物被批准用于 HCV 治疗的临床应用。然而，目前尚无治疗黄病毒感染的许可疗法，而唯一获得许可的登革热疫苗 Dengvaxia 仅限于具有预先存在的 DENV 免疫力的患者。与 NS5 聚合酶一样，NS3 催化区域在黄病毒科家族中是进化保守的，与属于该家族的其他蛋白酶具有强烈的结构相似性，因此是开发泛黄病毒疗法的有吸引力的靶标。在这项工作中，我们提出了一个包含 34 个哌嗪衍生小分子的文库，作为潜在的黄病毒科 NS3 蛋白酶抑制剂。该文库是通过基于特权结构的设计开发的，然后使用活病毒表型测定进行生物筛选，以确定每个化合物对 ZIKV 和 DENV 的半数最大抑制剂浓度（IC）。两种先导化合物 42 和 44 具有针对 ZIKV（IC6.6µM 和 1.9µM 分别）和 DENV（IC6.7µM 和 1.4µM 分别）的有前途的广谱活性和良好的安全性特征。此外，还进行了分子对接计算，以提供有关与 NS3 蛋白酶活性位点残基的关键相互作用的见解。
