Guangdong Provincial Engineering Laboratory of Biomass High Value Utilization, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou, China.
Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore.
Front Cell Infect Microbiol. 2022 Aug 9;12:959727. doi: 10.3389/fcimb.2022.959727. eCollection 2022.
Dengue virus is an important pathogen affecting global population while no specific treatment is available against this virus. Effort has been made to develop inhibitors through targeting viral nonstructural proteins such as NS3 and NS5 with enzymatic activities. No potent inhibitors entering clinical studies have been developed so far due to many challenges. The genome of dengue virus encodes four membrane-bound nonstructural proteins which do not possess any enzymatic activities. Studies have shown that the membrane protein-NS4B is a validated target for drug discovery and several NS4B inhibitors exhibited antiviral activities in various assays and entered preclinical studies.. Here, we summarize the recent studies on dengue NS4B protein. The structure and membrane topology of dengue NS4B derived from biochemical and biophysical studies are described. Function of NS4B through protein-protein interactions and some available NS4B inhibitors are summarized. Accumulated studies demonstrated that cell-based assays play important roles in developing NS4B inhibitors. Although the atomic structure of NS4B is not obtained, target-based drug discovery approach become feasible to develop NS4B inhibitors as recombinant NS4B protein is available.
登革热病毒是一种影响全球人口的重要病原体，但目前尚无针对该病毒的特效治疗方法。人们一直在努力通过针对具有酶活性的病毒非结构蛋白（如 NS3 和 NS5）来开发抑制剂。由于存在许多挑战，目前尚未开发出进入临床研究的强效抑制剂。登革热病毒的基因组编码四种膜结合的非结构蛋白，这些蛋白不具有任何酶活性。研究表明，膜蛋白 NS4B 是药物发现的一个有效靶点，几种 NS4B 抑制剂在各种检测中表现出抗病毒活性，并进入临床前研究。本文总结了登革热 NS4B 蛋白的最新研究进展。描述了从生化和生物物理研究中得出的登革热 NS4B 的结构和膜拓扑结构。通过蛋白-蛋白相互作用总结了 NS4B 的功能，以及一些现有的 NS4B 抑制剂。已有的研究表明，基于细胞的检测在开发 NS4B 抑制剂方面发挥着重要作用。尽管尚未获得 NS4B 的原子结构，但由于可获得重组 NS4B 蛋白，基于靶标的药物发现方法可用于开发 NS4B 抑制剂。
