Development of Glycodendrimers as Potential Anti-HIV Microbicide Agents

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 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.