基于水溶性棉酚衍生物骨架的新型HIV-1gp41膜融合抑制剂研究

In the face of the serious threat of HIV epidemic spreading from high-risk groups to the general population in our country, lack of effective anti-HIV drugs,it is especially urgent to develop novel anti-HIV durgs with the occurrence of single or multiple resistance to the drugs used. Recently,in our group,water soluble derivatives of gossypol were identified as novel small molecule HIV-1 fusion inhibitors targeting to gp41, which not only could fit inside the gp41 hydrophobic pocket but also promised good activity aganist the resistant HIV-1 strains and less cytotoxicity.Thus,it is suitable to study as a novel scaffold of HIV-1 gp41 fusion inhibitor. In the meantime, it was also reported that the N-terminal residues (Met-626 and Thr-627)adjacent to PBD in the potent HIV-1 fusion inhibitor peptides derived from the HIV-1gp41CHR adopted a unique hook-like structure(termed M-T hook),which played a critical role in binding stability and anti-HIV activity. Promisingly, the M-T hook confers the inhibitor to overcome drug resistance. In order to focuse on addressing the structure and function of the M-T hook and find novel stable and potent compounds against HIV, based upon the scaffold of water-soluble amino acid derivatives of gossypol, two types of novel compounds were designed,including novel compounds containing M-T hook or containing no M-T hook.The preliminary study results showed that some compounds had showed potent activities against HIV-1,including the resistant HIV-1strains.Compared with the compounds containing no M-T hook,some compounds containing M-T hook exhibited more potent anti-HIV-1 activities(3-5-fold). Therefore,we plan to synthesize novel compounds and investigate their activities against HIV-1 in vitro to find novel lead compounds.The mechanism of action of these novel compounds will be studied including inhibiting HIV-1fusion test, identifying the binding site of novel compounds on HIV-1gp41NHR by more detailed site-directed mutagenesis and investigating the binding mechanism by computer-assisted program.The crystal structure of novel compound complexed with HIV-1gp41 will be studied as well in order to guide the design of novel small molecule HIV-1gp41 fusion inhibtiors.

面对我国HIV疫情从高危人群向一般人群蔓延，有效防治药物不多，耐药性又不断发生，因而研制预防或治疗艾滋病药物显得尤为迫切。近年，我们发现水溶性棉酚衍生物是一种新型小分子HIV-1gp41融合抑制剂且低毒，可作为新骨架开展研究。另外，某些衍生于HIV-1gp41CHR的高活性多肽N端残基Met-626和Thr-627能形成独特勾状结构(M-T Hook)，可增强多肽与HIV-1gp41NHR表面疏水口袋结合力及其抗病毒活性。因而基于其骨架，引入M-T Hook而设计两类新化合物，初步研究显示某些含M-T Hook化合物较不含M-T Hook化合物活性提高3-5倍，并对多种耐药HIV-1病毒显示很强抗病毒活性。因此，我们拟合成两类化合物，通过抗HIV-1实验发现高活性化合物，探讨M-T Hook修饰作用，获得新化合物与HIV-1gp41复合物晶体结构，揭示其抗HIV-1融合机制，指导新药设计。

面对我国HIV疫情从高危人群向一般人群蔓延，有效防治药物不多，耐药性又不断发生， 因而研制预防或治疗艾滋病药物显得尤为迫切。近年，我们发现水溶性棉酚衍生物是一种新型小分子HIV-1gp41融合抑制剂且低毒，可作为新骨架开展研究。本课题以棉酚为新骨架设计一系列其简化合物或类似物，如联萘二甲酸衍生物、萘甲醛衍生物和萘甲酸衍生物等，从降低毒性和增强活性设计思路出发，用不同的氨基酸衍生物、二肽和5-氨基-四氮唑等特殊的胺模拟M-T hook作用对其进行修饰而制备了一系列新化合物。抗病毒实验结果发现某些氨基酸修饰联萘二甲酸衍生物、萘甲醛衍生物和萘甲酸衍生物等新化合物具有明显的降毒增效作用，如异亮氨酸衍生物等，优于M-T等二肽，其抗病毒作用与T20(恩夫韦肽, Fuzeon)相似，是作用在病毒感染细胞进入阶段，且通过氢键或静电作用以及疏水作用于gp41N36表面疏水口袋从而抑制6-HB六聚体形成。另外，5-氨基-四氮唑也有相似的修饰作用。这些结果为寻找新的抗HIV-1病毒药物提供了一条新思路并可指导抗病毒新药设计。