宿主细胞蛋白Tetherin可以抑制HIV-1等多种包膜病毒的释放，高效抑制病毒的复制。HIV-1编码的Vpu蛋白可以下调细胞表面的Tetherin，使得病毒逃脱宿主这一天然的抗病毒机制。有效地抑制病毒的拮抗能力，宿主细胞就可以利用Tetherin这一宿主限制因子抑制HIV-1的复制。Vpu下调Tetherine的分子机理研究及其在抗病毒药物研发上的应用是目前的研究热点和前沿。本课题组前期研究中首次发现了可以特异性阻断Vpu下调Tetherin的小分子化合物IMB-AZ和IMB-LA。本申请将研究小分子阻断Vpu下调Tetherin的分子机制，确定活性化合物的直接作用靶点，探索活性化合物的构效关系，建立活性化合物小分子和药物靶点相互作用的分子模型。这一工作不仅为以上述活性化合物为基础，发展作用机制独特的抗HIV-1药物先导物提供关键数据，而且将推动相关的病毒逃逸宿主天然免疫的基础研究。

Host factor tetherin is able to inhibit HIV-1 releaseing and thereby its replication. HIV-1 Vpu induces down-regulation of cell surface tetherin,and viruses therefore escape from the restrition effect of tetherin. In our prelimiary study, we have identified two small molecule compounds IMB-AZ and IMB-LA that specifically block Vpu-mediated down-regulation of tetherin. In this proposed work, we will investigate the mechanism how these compounds inhibit the down-regulation process, identify their direct target, explore their structure-activity relationship, and establish model of drug/target interaction. The objective of this work are to understand the mechanism of antiviral activity of the compound, and to promote the development of novel anti-HIV drug from the leading compounds.