Inhibitor Development against p7 Channel in Hepatitis C Virus.
Inhibitor Development against p7 Channel in Hepatitis C Virus.
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丙型肝炎病毒 p7 通道抑制剂的开发
DOI：
10.3390/molecules26051350
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发表时间：
2021-03-03
期刊：
影响因子：
--
通讯作者：
OuYang B
中科院分区：
文献类型：
--
作者：
Wei S;Hu X;Du L;Zhao L;Xue H;Liu C;Chou JJ;Zhong J;Tong Y;Wang S;OuYang B
丙型肝炎病毒（HCV）是慢性和严重肝脏疾病的主要原因。近年来直接作用的抗病毒药物在治疗HCV相关疾病方面取得了一定的临床成功，但HCV病毒的快速变异突出了开发新药的持续必要性。p7是来自HCV的病毒孔蛋白，已被寻求作为潜在的抗HCV药物靶标。几类化合物，如金刚烷胺和金刚乙胺已被证明对p7抑制。然而，这些化合物的功效并不高。在这里，我们筛选了一些新的p7抑制剂与金刚烷胺支架的抑制剂的发展。用核磁共振滴定法测定了42个ARD系列化合物的解离常数（Kd）。使用病毒产生测定进一步证实了两种最佳抑制剂ARD 87和ARD 112的功效。通过分子动力学模拟，分析了最强抑制剂的结合模式和结合稳定性。这些ARD系列化合物连同49个先前发表的化合物通过分子对接进一步分析。在结构相似的化合物中鉴定了关键药效团。我们的研究表明，不同的功能基团与抑制HCV p7的效力高度相关，其中疏水相互作用是抑制效力的主导力量。我们的研究结果为设计更高亲和力的p7抑制剂作为潜在的抗HCV候选药物提供了指导原则。
Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.
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影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
4.2
作者：
Hedskog, Charlotte;Parhy, Bandita;Svarovskaia, Evguenia S.
通讯作者：
Svarovskaia, Evguenia S.
影响因子：
6.4
作者：
Borgia, Sergio M.;Hedskog, Charlotte;Shafran, Stephen D.
通讯作者：
Shafran, Stephen D.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A
影响因子：
3.5
作者：
Griffin, SDC;Beales, LP;Rowlands, DJ
通讯作者：
Rowlands, DJ