Synthesis of Novel Water-Soluble Glycodendrimers as Anti-HIV Agents

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DESCRIPTION (provided by applicant): The goal of the proposed research entails the synthesis of glycodendrimers capable of binding to the HIV surface protein gp120, and blocking subsequent interactions with the host cell leading up to viral entry. Gp120 is present on the surface of HIV complexed with membrane protein gp41 as a heterotrimer. The gp120/gp41 complex, upon binding to cell surface CD4, undergoes a conformational change, exposing the N-terminal region of gp41. Gp120 next binds cell surface co-receptors via electrostatic interactions, that strengthen the virus-host cell interactions, allowing for subsequent gp41 fusion, pore formation, and ultimately, viral entry. It has been reported that the viral fusion/entry process is cooperative, requiring multiple copies of CD4, host cell co-receptors, and clustering of the gp41/gp120 heterotrimer. Due to the multivalent nature of the viral fusion/entry process, it is hypothesized that the glycodendrimers will be capable of binding to multiple copies of gp120 simultaneously, preventing viral entry. The shape, number of carbohydrates, and size of the glycodendrimers are expected to be the significant contributing factors determining the anti-HIV activity. The hypothesis will be tested through accomplishment of four specific aims. SA#1 describes the synthesis of interchangeable dendrimer linkers and differentially branched cores. SA#2 outlines the synthesis of discrete carbohydrate-linker conjugates, primed for coupling to the branched dendrimer cores. SA#3 depicts the construction of a variety of branched glycodendrimers to evaluate the specific architectural features necessary for optimum binding to gp120, and inhibition of viral infectivity, which will be evaluated in the fourth specific aim (SA#4). Preliminary research indicates that the synthetic methodologies are sound and that the target glycodendrimers can be synthesized and evaluated for their anti-HIV properties within the timeframe of the project. The proposed research seeks to fill a void in the anti- HIV drug arsenal by providing lead compounds specifically targeting viral gp120. Relevance: In the U.S., there are 850,000-950,000 HIV-infected people, with an additional 180,000-280,000 unaware they are HIV-positive. Due to adverse side-effects and decreased drug effectiveness caused by viral resistance, the development of new anti-HIV drugs is crucial in maintaining longevity and quality of life for infected individuals. This research seeks to develop a new class of anti-HIV drugs.