HIV膜融合抑制剂P-19的广谱机制研究

膜融合抑制剂阻断了艾滋病病毒感染的关键步骤，深入研究膜融合机制并据此研发新一代抗病毒药物成为当前的国际热点领域。基于我们发现的M-T钩子结构，设计了23个氨基酸的短肽HP23，其表现出很好的抑制活性。近期在短肽的基础上我们设计了一新型膜融合抑制剂P-19，其表现出对HIV不同种株的抑制活性，其中包括HIV-2，SIV等毒株。由于HIV-1和HIV-2的进化史不同，仅具有约50%同源性，而P-19表现出超级广谱的抑制活性，其作用机制可能存在特殊性。本课题拟对P-19进行深入系统的研究，包括抑制剂的广谱活性、形成6-HB核心结构的特殊性及结构生物学分析，在获得功能与结构信息的基础上，探讨广谱膜融合抑制剂P-19的独特作用机制。预期结果可能开辟新的研究热点，这对探索HIV膜融合机制以及研发新型艾滋病药物都具重要的科学意义。

The membrane fusion plays a key role during HIV infection process. Thus, it is highly important to elucidate the mechanism of HIV membrane fusion and to develop novel HIV fusion inhibitors. We recently discovered that the residues Met 626 and Thr 627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure. Based on M-T hook, we designed a 23-amino acid potent anti-HIV peptide named HP23 and it had high anti-HIV activity. Because of different evolutionary history, HIV-1 and HIV-2 only share about the 50% homology gene. The current anti HIV-1 drugs especially targeting membrane fusions have very low anti HIV-2 activity. On the basis of HP23, we designed a novel membrane fusion inhibitor P-19, which showed inhibitory activity against different strains of HIV, including HIV-2, SIV and other strains. So we ask that whether P-19‘s broad-spectrum antagonistic capacity is caused by the different membrane fusion mechanism? The aims of this proposal are to understand the antiviral mechanism of P-19 and to establish strategies for designing and optimizing HIV fusion inhibitors. Specifically, we will systemically study P-19 on its antiviral broad spectrum, the effect on the viral fusion capacity, the interaction with the viral target site as well as its structure. The important information about membrane fusion mechanism may open up new research focus and lay scientific foundation for developing novel anti-HIV drugs.