长效抗艾滋病新药艾博卫泰的结构生物学研究

Developed independently in China, albuvirtide(ABT)is the world's first long-acting anti-AIDS drug. It is currently under clinical trial. Binding with gp41 NHR in a dominant-negative manner, ABT intervenes the membrane fusion upon HIV entry.ABT is a 3-maleimimidropropionic acid(MPA)-modified peptide that irreversibly conjugate to serum albumin. Due to its long half-life in blood, it overcomes the disadvantages of current membrane-fusion-inhibitive peptides. However, the inhibition mechanisms of either ABT or inhibitors of this kind are not clear. No structural information is available on how albumin-conjugated ABT binds target. Lacking essential structural information constrained the development of this kind of inhibitors. Therefore, the proposer focuses on solving the structure of ABT/target complex. Based on proposer's previous study of biophysical property and broad anti-HIV activity of ABT, this research goes deeper onto ABT's mechanism. This research will demonstrate for the first time the structure of ABT/target complex by using techniques including X-ray crystallography and biomolecular small-angle X-ray scattering. The structural information will facilitate the understanding of the inhibition mechanism and the resistance mechanism of this kind of long-acting fusion inhibitors.

艾博卫泰（ABT）是由中国自主研发的、世界上首个长效抗艾滋病药物，目前处于临床试验阶段。ABT通过竞争性结合HIV gp41 NHR区段来阻断病毒入侵宿主细胞关键的膜融合过程。ABT是经马来酰亚胺丙酸修饰的多肽, 在血液中通过共价结合血清白蛋白发挥长效抗病毒作用,从而克服了现有多肽类膜融合药物在血液中不稳定、易降解的缺点。然而目前ABT及这一类长效抑制剂的作用机理尚不清楚，偶联一个分子量较大的血清白蛋白时药物与靶点的结合方式没有任何结构信息。鉴于结构信息的缺失制约了ABT及该类长效药物的研发，本研究聚焦于ABT与药物靶点复合物的结构生物学研究。在对ABT的理化性质与广谱抗病毒活性进行了初步分析的基础上，本研究拟利用X射线晶体学、生物大分子小角散射等多种技术手段，首次明确长效HIV膜融合抑制剂与靶点复合物的结构，将有助于阐明ABT的作用机理和耐药机制等诸多关键科学问题。