Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, SAR, China.
Sci Rep. 2017 Aug 30;7(1):10037. doi: 10.1038/s41598-017-08815-z.
Tylophorine analogs have been shown to exhibit diverse activities against cancer, inflammation, arthritis, and lupus in vivo. In this study, we demonstrated that two tylophorine analogs, DCB-3503 and rac-cryptopleurine, exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype 1b Con 1 isolate. The inhibition of HCV replication is at least partially mediated through cellular heat shock cognate protein 70 (Hsc70). Hsc70 associates with the HCV replication complex by primarily binding to the poly U/UC motifs in HCV RNA. The interaction of DCB-3503 and rac-cryptopleurine with Hsc70 promotes the ATP hydrolysis activity of Hsc70 in the presence of the 3' poly U/UC motif of HCV RNA. Regulating the ATPase activity of Hsc70 may be one of the mechanisms by which tylophorine analogs inhibit HCV replication. This study demonstrates the novel anti-HCV activity of tylophorine analogs. Our results also highlight the importance of Hsc70 in HCV replication.
苝双呋喃类化合物已被证明具有多种抗癌、抗炎、抗关节炎和抗狼疮的活性。在本研究中，我们证明了两种苝双呋喃类化合物，DCB-3503 和 rac-隐色孔雀花碱，对基因型 1b Con1 分离株的丙型肝炎病毒（HCV）复制具有很强的抑制活性。HCV 复制的抑制至少部分是通过细胞热休克同源蛋白 70（Hsc70）介导的。Hsc70 主要通过与 HCV RNA 中的多 U/UC 基序结合，与 HCV 复制复合物结合。DCB-3503 和 rac-隐色孔雀花碱与 Hsc70 的相互作用促进了 HCV RNA 3'多 U/UC 基序存在时 Hsc70 的 ATP 水解活性。调节 Hsc70 的 ATPase 活性可能是苝双呋喃类化合物抑制 HCV 复制的机制之一。本研究证明了苝双呋喃类化合物的新型抗 HCV 活性。我们的结果还强调了 Hsc70 在 HCV 复制中的重要性。
