Lescar Julien, Luo Dahai, Xu Ting, Sampath Aruna, Lim Siew Pheng, Canard Bruno, Vasudevan Subhash G
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Antiviral Res. 2008 Nov;80(2):94-101. doi: 10.1016/j.antiviral.2008.07.001. Epub 2008 Jul 30.
New treatments are urgently needed to combat the increasing number of dengue fever cases in endemic countries as well as amongst a large number of travellers from non-endemic countries. Of the 10 virus encoded proteins, NS3 (non-structural 3) and NS5 carry out all the enzymatic activities needed for polyprotein processing and genome replication, and are considered to be amenable to antiviral inhibition by analogy with successes for similar targets in human immunodeficiency virus and hepatitis C virus. The multifunctional NS3 protein of flavivirus forms a non-covalent complex with the NS2B cofactor and contains the serine-protease activity domain at its N-terminus that is responsible for proteolytic processing of the viral polyprotein and a ATPase/helicase and RNA triphosphatase at its C-terminal end that are essential for RNA replication. In addition, NS3 seems to be also involved in virus assembly. This review covers the recent biochemical and structural advances on the NS2B-NS3 protease-helicase and presents an outlook for the development of small molecules as antiviral drugs targeting this fascinating multifunctional protein.
在登革热流行国家以及大量来自非流行国家的旅行者中，登革热病例不断增加，因此迫切需要新的治疗方法。在病毒编码的10种蛋白质中，NS3（非结构蛋白3）和NS5执行多蛋白加工和基因组复制所需的所有酶促活性，并且通过与人类免疫缺陷病毒和丙型肝炎病毒中类似靶点的成功案例类比，被认为适合进行抗病毒抑制。黄病毒的多功能NS3蛋白与NS2B辅因子形成非共价复合物，在其N端含有丝氨酸蛋白酶活性结构域，负责病毒多蛋白的蛋白水解加工，在其C端含有ATP酶/解旋酶和RNA三磷酸酶，这些对于RNA复制至关重要。此外，NS3似乎也参与病毒组装。本综述涵盖了NS2B-NS3蛋白酶-解旋酶的最新生化和结构进展，并展望了开发针对这种迷人的多功能蛋白的小分子抗病毒药物。
