摘要
丙型肝炎病毒(HCV)是丙型肝炎传染病的病原体,主要影响肝脏,就其严重性而言,一般会持续几周或直至终身。HCV的RNA基因组长9.6 kb,编码约3000个氨基酸的多聚蛋白,必须同时经过宿主和病毒蛋白酶的处理分别形成结构型(S)和非结构型(NS)蛋白。在此我们关注带有活化因子NS4A的丝氨酸蛋白酶NS3,即NS3/4A,一直被视为抗HCV治疗的最有吸引力的靶点之一。虽然没有可用的HCV疫苗,但仅是抗病毒药物就能够治愈约90%的患有丙型肝炎感染的病人。但另一方面,这些药物的疗效可能会由于过快的用药和交叉耐药性而受到阻碍。到目前为止,所有的HCV NS3/4A抑制剂主要是基于肽段的化合物,而这些化合物都源于NS3/4A底物的裂解产物。特别是大环肽已迅速成为一个经典的用于治疗HCV感染的NS3/4A蛋白酶抑制剂。本文综述了大环肽抗HCV NS3/4A蛋白酶的发展过程,以及临床上一些开发自线性肽段的重要抑制剂,这些抑制剂都是在过去的12年(2003-2015年)中通过所有的途径发现的,包括实验室合成的方法,虚拟筛选和基于结构的分子对接结构研究。我们强调设计背后的原理、构效关系研究,以及抑制剂的作用机制和大环肽对细胞的影响。
关键词: Hepatitis C virus
Current Medicinal Chemistry
Title:Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry
Volume: 23 Issue: 29
Author(s): Thanigaimalai Pillaiyar, Vigneshwaran Namasivayam, Manoj Manickam
Affiliation:
关键词: Hepatitis C virus
摘要: Hepatitis C virus (HCV) is a causative agent of hepatitis C infectious disease that primarily affects the liver, ranging in severity from a mild illness lasting a few weeks to a lifelong illness. The 9.6 kb RNA genome of HCV encodes approximately 3000 amino acid polyprotein that must be processed by host and viral proteases into both structural (S) and non-structural (NS) proteins, respectively. Targeting the serine protease NS3 with an activating factor NS4A, i.e., NS3/4A has been considered as one of the most attractive targets for the development of anti-HCV therapy. Although there is no vaccine available, antiviral medicines cure approximately 90% of the persons with hepatitis C infection. On the other hand, efficacy of these medications can be hampered due to the rapid drug and cross resistances. To date, all developed HCV NS3/4A inhibitors are mainly peptide-based compounds derived from the cleavage products of substrate. Specifically macrocyclic peptidomimetics have rapidly emerged as a classical NS3/4A protease inhibitors for treating the HCV infection. This review highlights the development of macrocyclic anti-HCV NS3/4A protease, as well as clinically important inhibitors developed from linear peptides, discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, virtual screening and structure-based molecular docking studies. We emphasize the rationale behind the design, study of structure-activity relationships, and mechanism of inhibitions and cellular effect of the macrocyclic inhibitors.
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Cite this article as:
Thanigaimalai Pillaiyar, Vigneshwaran Namasivayam, Manoj Manickam , Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry, Current Medicinal Chemistry 2016; 23 (29) . https://dx.doi.org/10.2174/0929867323666160510122525
DOI https://dx.doi.org/10.2174/0929867323666160510122525 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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