以整合酶-LEDGF/p75相互作用为靶点的抗HIV药物高通量筛选

HIV整合酶(IN)与宿主细胞蛋白LEDGF/p75相互作用是HIV复制周期中不可或缺的重要环节，阻断该相互作用能有效抑制病毒复制，被认为是抗HIV药物研发的重要靶点。从药用植物内生真菌代谢产物中筛选药物，具有来源广泛、可能发现全新化合物、可持续利用、能大规模工业化生产和质量可控等优点。本项目以IN-LEDGF/p75相互作用为靶点，建立新的检测LEDGF/p75-IN相互作用的高通量方法，开展IN-LEDGF/p75相互作用研究和抑制剂研究。从药用植物内生真菌代谢产物中筛选获得能有效抑制IN-LEDGF/p75相互作用的样品，结合化学分离和分析方法，从活性样品中分离出有效部位或活性单体并跟踪测试活性和确定其成分或分子结构，最终结合细胞病毒实验，对样品的抗病毒活性、细胞毒性等进行分析，提出新的抗HIV活性物质。该项目将为HIV药物研究和药用植物内生真菌中生物活性物质开发提供有益探索。

The interaction between HIV integrase (IN) and the host celluar protein LEDGF/p75 plays essential roles in HIV replication cycle. The involvemnt of LEDGF/p75 in several aspects of HIV IN function and the blocking of IN-LEDGF/p75 interaction effectively inhibits HIV replication validates the IN-LEDGF/p75 interaction as a potential target for anti-HIV drug development. Drug screening using endophytic fungi metabolites from medicinal plants as the drug sources have the advantages of rich resource availability, potentiality of disclosing new compounds, environment-friendly, sustainable utilization, massive production scalability and quality controllability. In this project, novel high-throughput assays for IN-LEDGF/p75 interaction will be developed and applied for the studies of IN-LEDGF/p75 interaction as well as anti-HIV durg targeting IN-LEDGF/p75 interaction. Metabolites of endophytic fungi from medicinal plants will be used as the drug source, and samples effectively inhibiting the IN-LEDGF/p75 interaction will be screened out. Subsequently, effective fractions or monomeric compound from active samples will be seperated, purified, and analyzed. Finally, the antiviral activity and toxicity of active samples will be further analyzed by cellular antiviral assays, and novel HIV inhibitors will be achieved. The outcome of this project is benefitial for the studies of anti-HIV drug development and the exploitation of bioactive substances of endophytic fungi from medicinal plants.