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Optimization of Small Molecules That Sensitize HIV‑1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity

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journal contribution
posted on 18.11.2019 by Melissa C. Grenier, Shilei Ding, Dani Vézina, Jean-Philippe Chapleau, William D. Tolbert, Rebekah Sherburn, Arne Schön, Sambasivarao Somisetti, Cameron F. Abrams, Marzena Pazgier, Andrés Finzi, Amos B. Smith
With approximately 37 million people living with HIV worldwide and an estimated 2 million new infections reported each year, the need to derive novel strategies aimed at eradicating HIV-1 infection remains a critical worldwide challenge. One potential strategy would involve eliminating infected cells via antibody-dependent cellular cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to conceal epitopes located in its envelope glycoprotein (Env) that are recognized by ADCC-mediating antibodies present in sera from HIV-1 infected individuals. Our aim is to circumvent this evasion via the development of small molecules that expose relevant anti-Env epitopes and sensitize HIV-1 infected cells to ADCC. Rapid elaboration of an initial screening hit using parallel synthesis and structure-based optimization has led to the development of potent small molecules that elicit this humoral response. Efforts to increase the ADCC activity of this class of small molecules with the aim of increasing their therapeutic potential was based on our recent cocrystal structures with gp120 core.