多域泛素化连接酶UHRF1作为HIV潜伏逆转剂新靶点的研究

HIV潜伏储存库的存在是导致艾滋病无法被彻底治愈的关键，而挖掘新的关键宿主因子并研究其与潜伏病毒蛋白之间的相互作用，对彻底清除HIV潜伏库至关重要。课题组前期研究发现，一种多域泛素化连接酶UHRF1在HIV潜伏感染细胞中表达显著上调，极有可能参与调控HIV潜伏，但其如何发挥调控作用的尚未可知。本课题拟通过研究UHRF1对HIV转录复制、潜伏感染活化的调控作用和分子机制，旨在明确UHRF1作为HIV潜伏逆转剂药物新靶点的可能性；进一步以UHRF1抑制剂NSC232003为母核设计并合成一系列小分子化合物，评价其细胞毒性及激活潜伏HIV的活性和机制，以期开发出一类以UHRF1为靶点的具有自主知识产权的新型高效小分子HIV潜伏逆转剂，为实现HIV治愈或无药生存的HIV“功能性”治愈奠定基础。

To date, HIV cure has not yet been established due to viral reservoir which leads to durably latent HIV infection. Accumulated evidence show cellular factors are required to maintain proviral latency, so it is extremely important to explore novel host factors involved in the regulation of HIV latency which may provide potential drug targets to eliminate the persistent reservoir. Our previous studies show that ubiquitin-like with PHD and RING finger domains 1 (UHRF1) expression was obviously up-regulated in latently HIV-infected cells, indicating its promising role in the regulation of HIV latency, however, the underlying mechanism is unclear. This project attempts to explore the possibility of UHRF1 as a novel target for the development of latency reversing agents (LRAs) by elucidating the molecular mechanism of UHRF1 in the regulation of HIV transcription and reactivation of latent HIV infection. Further study will focus on the optimization of an UHRF1 inhibitor, NSC232003, as a lead compound in order to develop a series of novel small-molecule LRAs with higher efficiency and lower cytotoxicity. To sum up, this study aims to evaluate the potential of UHRF1 as a novel target to develop a novel class of highly effective LRAs with independent intellectual property rights which may provide potential advances into HIV cure or "functional cure" of HIV infection.