Novartis Institutes of Biomedical Research, Cambridge, MA 02139, USA.
Virology. 2010 Feb 5;397(1):43-55. doi: 10.1016/j.virol.2009.10.043. Epub 2009 Nov 24.
Three cyclophilin inhibitors (DEBIO-025, SCY635, and NIM811) are currently in clinical trials for hepatitis C therapy. The mechanism of action of these, however, is not completely understood. There are at least 16 cyclophilins expressed in human cells which are involved in a diverse set of cellular processes. Large-scale siRNA experiments, chemoproteomic assays with cyclophilin binding compounds, and mRNA profiling of HCV replicon containing cells were used to identify the cyclophilins that are instrumental to HCV replication. The previously reported cyclophilin A was confirmed and additional cyclophilin containing pathways were identified. Together, the experiments provide strong evidence that NIM811 reduces viral replication by inhibition of multiple cyclophilins and pathways with protein trafficking as the most strongly and persistently affected pathway.
三种亲环素抑制剂（DEBIO-025、SCY635 和 NIM811）目前正在进行丙型肝炎治疗的临床试验。然而，这些药物的作用机制尚不完全清楚。人类细胞中至少表达有 16 种亲环素，它们参与了多种细胞过程。大规模的 siRNA 实验、亲环素结合化合物的化学蛋白质组学测定以及含有 HCV 复制子的细胞的 mRNA 分析，用于鉴定对 HCV 复制至关重要的亲环素。先前报道的亲环素 A 得到了证实，并确定了其他含有亲环素的途径。总的来说，这些实验为 NIM811 通过抑制多种亲环素和蛋白转运途径来降低病毒复制提供了有力证据，其中蛋白转运途径受到的影响最为强烈和持久。
