双靶点HIV抑制剂的设计、合成及活性研究

AIDS has not been effectively resolved since it was discovered, one reason is that HIV is highly resistant to traditional drugs. It is the urgent need to develop novel high efficiency and long-lasting anti-HIV drugs for AIDS prevention and control. During the early phase of HIV infection, dendritic cells (DCs) play an essential role in the contribution to viral dissemination by their ability to capture and transport virions into CD4+ T cells, the main mechanism of which is the interaction between the lectin on DCs (DC-SIGN) and the high mannose on virions. Base on the interaction and the result of previous project (grant nos. 81001389，glycosylation of anti-HIV polypeptide T20 results in significant extension half-life), we plan to site-specific glycosylation of anti-HIV peptides with DC-SIGN specific oligosaccharides to afford dual-targeting anti-HIV glycopeptides, and the bioactivity, and the pharmacokinetics will be studied in order to achieve novel anti-HIV inhibitors with extended half-life and increased activity. Compared with the traditional anti-HIV drugs, the glycopeptides to be obtained in this project are novel dual-targeting inhibitors, as the glycoside moiety competitively bind to DC-SIGN to inhibit capture of HIV by DCs, and the peptide moiety binds to HIV envelope protein gp41 to inhibit virus entry into T-cells. This project will obtain series of potential anti-HIV drug candidates and may provide a valuable example of discovery of novel HIV inhibitor.

艾滋病自发现以来一直没有得到有效的解决，部分原因在于HIV极易对传统药物产生耐药性，如何快速获得高效、长效的新型抗HIV药物是艾滋病防控面临的重要问题。HIV的感染首先依赖于树突细胞（DC）的呈递，DC通过其表面蛋白DC-SIGN与病毒表面甘露糖链的结合实现对病毒的捕获内吞，而后将病毒呈递给靶细胞。本项目根据上述糖链与蛋白之间的互作，以及前一个项目的研究结果（寡糖修饰抗HIV多肽药物T20可显著延长其药效），拟用DC-SIGN特异性的糖链定点修饰抗HIV多肽，并进行抑制活性、作用机制及药代研究，以期获得药效延长、活性增强的抗HIV糖肽。与传统的抗HIV药物相比，本项目拟获得的糖肽是一种新型的双靶点药物，其糖链可与病毒竞争性结合DC-SIGN，多肽可作用于病毒的囊膜蛋白gp41，这种双靶点作用不仅有望提高药物的活性和稳定性，也有可能解决多肽的耐药问题，并为发展新一代抗HIV药物提供前期基础。

艾滋病自发现以来一直没有得到有效的解决，部分原因在于HIV极易对传统药物产生耐药性，如何快速获得高效、长效的新型抗HIV药物是艾滋病防控面临的重要问题。HIV的感染首先依赖于树突细胞（DC）的呈递，DC通过其表面蛋白DC-SIGN与病毒表面甘露糖链的结合实现对病毒的捕获内吞，而后将病毒呈递给靶细胞。本项目根据上述糖链与蛋白之间的互作，以及前一个项目的研究结果（寡糖修饰抗HIV多肽药物T20可显著延长其药效），用DC-SIGN特异性的糖链——不同长度的甘露寡糖分别在不同位点定点修饰抗HIV多肽T20和C34，得到12种糖肽，并从分子水平验证了其双靶点作用：糖链可与病毒竞争性结合DC表面的DC-SIGN，多肽部分可抑制HIV的膜融合过程。并从细胞水平评估了其双靶点抗病毒活性。并对体外筛选得到的两种高活性糖肽进行了大鼠体内药代学研究。实验结果证明，本项目策略修饰得到的糖肽不仅显著改善了多肽的水溶性，提高了其抗病毒活性，同时还可延长其体内作用时间，是一种新型的、具有进一步研发潜力的双靶点HIV抑制剂。本项目完成计划书的研究目标，项目的完成为抗艾滋药物的研发提供了一条新思路，为发展新一代抗HIV药物提供了前期基础。