With approximately 36.9 million people living with HIV worldwide and with 2.0 million new infections reported each year, the need for novel strategies, both to prevent transmission and to suppress viral reservoirs remains a critical priority. Over the past several years, our highly interdisciplinary NIH Project Team (GM 56550) has developed a detailed understanding of both the structural/functional mechanism of the HIV-1 glycoprotein envelope (Env) complex in the viral entry process, that has led to a potential long-term strategy for intervention. Based on the initial observations by Debnath and colleagues at the New York Blood Center, we have designed and optimized a series of potent, broadly active small-molecule CD4-mimic entry inhibitors exemplified by (+)-(<i>R,R</i>)-BNM-IV-147. Encouraging viral neutralization results, including direct viral entry inhibition, rely on the demonstrated ability of the bound CD4-mimic entry inhibitors to expose epitopes recognized by antibodies present in HIV-infected individuals, that in turn enhance the efficacy of the immune response against both the HIV virus itself and against infected cells.

Design, synthesis and biological evaluation of small-molecule inhibitors of HIV-1 entry: A potential long-term strategy for curbing the AIDS pandemic

253rd National Meeting (2017)

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