Development of Glycodendrimers as Potential Anti-HIV Microbicide Agents

糖树聚合物作为潜在抗 HIV 杀菌剂的开发

基本信息

批准号：
9140913
负责人：
KATHERINE D MCREYNOLDS
金额：
$ 10.58万
依托单位：
CALIFORNIA STATE UNIVERSITY SACRAMENTO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9140913
关键词：
AIDS/HIV problem Acids Adopted Anti-HIV Agents Automobile Driving Binding Biological Biological Assay CCR5 gene CXCR4 gene Cell surface Cells Cellular Structures Chemistry Coitus Dendrimers Development Disease Electrostatics Enzyme-Linked Immunosorbent Assay Enzymes Glycoside Hydrolases HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Half-Life Heparan Sulfate Proteoglycan Hydrazones Individual Infection Inorganic Sulfates Laboratories Lead Life Link Literature Local Microbicides Mediating Membrane Proteins Methodology Methods Modification Molecular Oligosaccharides Organic solvent product Outcome Oximes Polymers Prevention Prevention strategy Procedures Process Property Reaction Reaction Time Research Research Priority Running Solvents Staging Strategic Planning Structure Time Toxic effect United States National Institutes of Health Universities Unspecified or Sulfate Ion Sulfates Vaccines Viral Viral Physiology Vulnerable Populations Water Woman Work anti-HIV microbicide base chemokine cost effective cytotoxicity design drug candidate improved innovation microbicide microwave electromagnetic radiation novel pathogen prevent prophylactic public health relevance screening sugar sulfation transmission process virus development

项目摘要

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.

描述（由适用提供）：全世界大约有3700万人患有艾滋病毒/艾滋病。这些人中有多达一半的人没有意识到自己的艾滋病毒状况，并且主要是通过性交来传播疾病。由于没有可防止病毒传播的疫苗，因此其他预防策略的发展至关重要。 McReynolds实验室中的工作集中在新型糖结二聚体分子的发展上，作为潜在的局部抗HIV杀菌剂。当前的NIH战略计划列出了抗HIV微生物剂的发展为2016财政年度的研究优先事项。所提出的糖胶质聚合物分子是关键的聚苯式宿主细胞表面结构，趋化因子共肽（CXCR4和CCR5）以及无处不在的细胞表面分子，乙酰肝素硫酸盐蛋白糖蛋白酶（HSPGS）的分子模拟物。这些宿主细胞结构与三聚体和多边形HIV-1表面蛋白GP120之间的静电相互作用发生了多种发生，并导致病毒附着并最终导致感染。所提出的糖结基聚合物的设计既是多价和聚苯基，因此有能力阻止这些宿主细胞到病毒的接触点，并防止最早的附着和感染阶段发生。该项目有两个主要目标。首先是由天然或合成寡糖组成的独特多价值糖胶质聚体的合成，它们将作为宿主细胞趋化因子共受体/HSPG的分子模拟物的作用。第二个是将绿色化学原理采用到合成方法中。绿色化学代表了一种多功能，高效且具有成本效益的策略，可以以更少的步骤和更好的产量制作糖胶质体，同时最大程度地减少了使用有机溶液的使用并缩短反应时间。这将导致迅速发展抗HIV活动的化合物。将掺入糖结核定体合成中的绿色方法是：1。通过减少使用保护组的使用并掺入化学选择性连锁，对反应步骤数量的数量最小化。 2。运行反应整洁，或用水作为溶液。 3。掺入酶催化反应。 4。使用微波介导的反应缩短反应时间并提高产量。该项目的成功完成有可能产生一种新的杀菌剂剂，能够预防全球数百万个新的HIV感染。