ml9b00445_si_001.pdf (2.82 MB)
Optimization of Small Molecules That Sensitize HIV‑1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity
Version 2 2019-11-18, 21:29
Version 1 2019-11-15, 15:06
journal contribution
posted on 2019-11-18, 21:29 authored 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. SmithWith 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.