Development of Glycodendrimers as Potential Anti-HIV Microbicide Agents

 描述(申请人提供)：全球约有3700万艾滋病毒/艾滋病患者。这些人中多达一半的人不知道自己的艾滋病毒状况，并在不知情的情况下传播疾病，主要是通过性交。由于目前还没有预防病毒传播的疫苗，因此制定其他预防策略至关重要。麦克雷诺实验室的工作重点是开发新型糖树状大分子分子，作为潜在的局部抗艾滋病毒杀菌剂。目前的NIH战略计划将开发抗艾滋病毒杀菌剂列为2016财年的研究重点。所提出的糖树状分子是关键的多阴离子宿主细胞表面结构的分子模拟，趋化因子辅助受体(CXCR4和CCR5)，以及普遍存在的细胞表面分子，硫酸乙酰肝素蛋白多糖(HSPGs)。这些宿主细胞结构与三聚体和多聚体HIV-1表面蛋白gp120之间的静电相互作用以多价方式发生，并导致病毒附着，最终导致感染。 建议的糖树状大分子既是多价的又是多阴离子的，因此将有能力阻止这些宿主细胞与病毒的接触点，并防止最初的附着和感染阶段的发生。该项目有两个主要目标。第一个是合成独特的多价多阴离子糖树状大分子，它由天然或合成的寡糖组成，将作为宿主细胞趋化因子辅助受体/热休克蛋白的分子模拟物。二是将绿色化学原理引入合成方法论。绿色化学代表了一种通用、高效和成本效益高的策略，可以在减少有机溶剂使用和缩短反应时间的同时，以更少的步骤和更好的产率制造糖树枝状大分子。这将导致加快开发具有更好的抗艾滋病毒活性的化合物。将用于合成糖树状大分子的绿色方法是：1.通过减少保护基团的使用和引入化学选择性键来最小化反应步骤的数量。2.运行反应整齐，或以水为溶剂。3.结合酶催化反应。4.采用微波辅助反应，缩短了反应时间，提高了产率。该项目的成功完成有可能产生一类新的杀微生物剂，能够预防全世界数百万新的艾滋病毒感染。

 DESCRIPTION (provided by applicant): There are approximately 37 million people living with HIV/AIDS worldwide. Up to half of these individuals are unaware of their HIV status and are unknowingly spreading the disease, primarily through sexual intercourse. As there is no vaccine available to prevent transmission of the virus, the development of other preventative strategies is of critical importance. Work in the McReynolds laboratory is focused on the development of novel glycodendrimer-based molecules as potential topical anti-HIV microbicide agents. The current NIH strategic plan lists the development of anti-HIV microbicides as a fiscal year 2016 research priority. The proposed glycodendrimer molecules are molecular mimics of key polyanionic host cell surface structures, the chemokine coreceptors (CXCR4 and CCR5), as well as the ubiquitous cell surface molecules, heparan sulfate proteoglycans (HSPGs). The electrostatic interactions between these host cell structures and the trimeric and polybasic HIV-1 surface protein, gp120, occur multivalently and lead to viral attachment and ultimately, infection. The proposed glycodendrimers are designed to be both multivalent and polyanionic and therefore will have the capacity to block these host cell-to-viral points of contact and prevent th earliest stages of attachment and infection from occurring. There are two primary objectives of the project. The first is the synthesis of unique multivalent polyanionic glycodendrimers comprised of either native or synthetic oligosaccharides, which will function as molecular mimics of host cell chemokine coreceptors/HSPGs. The second is to adopt principles of green chemistry into the synthetic methodologies. Green chemistry represents a versatile, efficient and cost effective strategy to make glycodendrimers in fewer steps and in better yields, all while minimizing the use of organic solvents and shortening the reaction times. This will lead to the expedited development of compounds with improved anti- HIV activities. The green methods that will be incorporated into the synthesis of the glycodendrimers are: 1. Minimization of the number of reaction steps by decreasing the use of protecting groups and incorporation of a chemoselective linkage. 2. Running reactions neat, or with water as a solvent. 3. Incorporating enzyme- catalyzed reactions. 4. Using microwave-mediated reactions to shorten the reaction times and improve the yields. Successful completion of this project has the potential to yield a new class of microbicide agents capable of preventing millions of new HIV infections worldwide.