HIV进入抑制剂是颇具前景的新机制抗艾药物，包膜蛋白亚基gp41是其重要的作用靶点。深海放线菌是药物资源宝藏，为筛选小分子HIV进入抑制剂提供新的来源。我们前期在南海深海放线菌中筛选到了具有抑制gp41的活性菌株，并从中发现了潜在新菌种和结构新颖的活性次生代谢产物。因此，本项目采用适合海洋微生物发酵物的改良ELISA法进行gp41抑制活性筛选，并以此为导向进行目标放线菌高盐胁迫等发酵条件的优化、次生代谢产物的活性导向分离和结构鉴定，再采用非感染细胞融合筛选法和HIV-1假病毒体系，对获得的gp41抑制剂进行HIV进入抑制活性筛选，最后进行目标产物的定向发酵和定向分离制备。本项目立足于丰富而特殊的南海深海放线菌资源，以gp41为筛选靶点有目标地开展HIV进入抑制剂的筛选，为抗HIV药物研发提供更多新作用机制、结构新颖且有药源保障的先导化合物，也为深入挖掘我国南海深海药用微生物资源奠定基础。

HIV entry inhibitors represent a new generation of antivirals for the treatment of HIV infection, by blocking the HIV entry into the target cells. Screening the small molecule HIV entry inhibitors targeting gp41 from natural products is the promising approach to develop new anti-HIV agents. Actinomycetes from deep-sea are considered as a promising source for the discovery of pharmaceutical active substances. In our previous research, several actinomycetes from deep-sea sediments of the South China Sea were discovered with their activities of inhibiting gp41 six-helix bundle (6-HB) core structure formation. The results prompt us to search the HIV entry inhibitors targeting gp41 from these actinomycetes. In this project, the improved ELISA methods for inhibiting gp41 will be used as the guide for the fermentation optimization of the target strains and the activity-oriented separation of the secondary metabolites. Then, the non-infectious assay for HIV Env-induced cell-cell fusion and HIV-1 pseudovirus-based infection assay will be applied to screen the entry inhibitors targeting gp41 in deep-sea mactinomycetes for the first time. Our research could provide the novel and abundant lead compounds with new mechanism for development of anti-HIV agents.