包膜蛋白亚基gp41 是HIV进入抑制剂重要的作用靶点。申请人前期从一株海洋真菌中分离了一系列的结构新颖的二倍半萜类化合物，其中主产物terpestacin可以抑制导致HIV病灶的细胞合胞体的形成和抑制血管增生的作用, 合胞体的形成与gp41构型的变化紧密相关。本项目拟对该菌进行OSMAC策略培养，结合LC-MS和HPLC-DAD方法快速定向分离和富集结构多样的该类化合物，借助计算机虚拟筛选技术，进行结构修饰，获取多样的结构衍生物，通过改良ELISA 法进行gp41 抑制活性筛选，进一步采用非感染细胞融合筛选法，对gp41 抑制剂进行HIV进入抑制活性筛选。本项目立足于我国南海丰富而特殊的真菌资源，有目标地开展HIV 进入抑制剂的筛选，为抗HIV 药物研发提供结构新颖和具有新作用机制的先导化合物，也为深入挖掘我国南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. In our previous research, several novel sesterterpenes were isolated and characterized from marine fungus Arthrinium sp. SCSIO41221 of the South China Sea. As main product, terpestacin was reported to be a potent inhibitor (ID50 0.46 μg/mL−1) of the formation of syncytia, which are multinucleated cells that account in part for the pathology of HIV infection, and to be an angiogenesis inhibitor both in bovine aortic endothelial cells and in chorioallantoic membrane from chick embryos. The HIV-1 gp41 (glycoprotein 41) core plays a critical role in HIV-1 envelope glycoprotein-mediated syncytium formation. This progam aimed at the OSMAC strategy for this fungus to discover and gather the sesterterpenes. Based on the Reverse Virtual Screening, more structural analogues will be acquired by the structural modification. The active compounds will be founded in these sesterterpenes with the improved ELISA methods for inhibiting gp41. Then, the non-infectious assay for HIV Env-induced cell-cell fusion will be applied to screen the entry inhibitors targeting gp41. In general, through the investigation of this project, the novel and abundant lead compounds with new mechanism for development of anti-HIV agents could be discovered from marine fungi.