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

• 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
• 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

 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（由申请人提供）：全世界约有3700万艾滋病毒/艾滋病感染者。这些人中多达一半不知道自己感染了艾滋病毒，并在不知不觉中传播了这种疾病，主要是通过性交。由于没有疫苗可以预防病毒的传播，因此制定其他预防战略至关重要。McReynolds实验室的工作重点是开发新型的基于糖树枝状聚合物的分子，作为潜在的局部抗HIV杀微生物剂。目前的NIH战略计划将开发抗HIV杀微生物剂列为2016财年的研究重点。 所提出的glycodendrimer分子是关键聚阴离子宿主细胞表面结构、趋化因子辅助受体（CXCR 4和CCR 5）以及普遍存在的细胞表面分子硫酸乙酰肝素蛋白聚糖（HSPG）的分子模拟物。这些宿主细胞结构与三聚体和多碱基HIV-1表面蛋白gp 120之间的静电相互作用以多价方式发生，并导致病毒附着并最终感染。 所提出的糖树枝状聚合物被设计为多价和聚阴离子的，因此将具有阻断这些宿主细胞与病毒接触点的能力，并防止最早阶段的附着和感染发生。 该项目有两个主要目标。第一个是合成独特的多价聚阴离子glycodendrimers包括天然或合成的寡糖，这将作为宿主细胞趋化因子辅助受体/HSPGs的分子模拟物。二是将绿色化学的原理引入到合成方法中。绿色化学代表了一种通用的、有效的和成本有效的策略，以更少的步骤和更好的产率制备糖树枝状聚合物，同时最大限度地减少有机溶剂的使用并缩短反应时间。这将加速开发具有改善的抗HIV活性的化合物。将并入糖树枝状聚合物合成的绿色方法是：1.通过减少保护基的使用和引入化学选择性连接来最小化反应步骤的数目。2.纯反应或用水作为溶剂进行反应。3.简化酶催化反应。4.利用微波介导反应，缩短反应时间，提高产率。 该项目的成功完成有可能产生一种新的杀微生物剂，能够预防全世界数百万新的艾滋病毒感染。