丙型肝炎病毒NS3/4A丝氨酸蛋白酶抑制剂系列的发现及其结构多样性，最终产生临床候选药物IDX320。
Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.
作者信息
Parsy Christophe C, Alexandre François-René, Bidau Valérie, Bonnaterre Florence, Brandt Guillaume, Caillet Catherine, Cappelle Sylvie, Chaves Dominique, Convard Thierry, Derock Michel, Gloux Damien, Griffon Yann, Lallos Lisa B, Leroy Frederic, Liuzzi Michel, Loi Anna-Giulia, Moulat Laure, Chiara Musiu, Rahali Houcine, Roques Virginie, Rosinovsky Elodie, Savin Simon, Seifer Maria, Standring David, Surleraux Dominique
机构信息
IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
IDENIX, a wholly-owned subsidiary of Merck & Co, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
出版信息
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5427-36. doi: 10.1016/j.bmcl.2015.09.009. Epub 2015 Sep 5.
Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.
通过模拟在BILN2061中发现的脯氨酸基序对P2区域进行探索，从而发现了两个系列的强效丙型肝炎病毒NS3/4A蛋白酶抑制剂。与NS3/4A蛋白结合的配体的X射线晶体结构以及通过基于结构的设计和建模对喹啉杂环区域进行的调节，实现了酶活性和细胞活性的优化。这项研究促成了临床候选药物IDX320的选定，该药物在各种物种中具有良好的基因型覆盖范围和药代动力学特性。
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