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Journal article
A New Family of Small-Molecule CD4-Mimetic Compounds Contacts Highly Conserved Aspartic Acid 368 of HIV-1 gp120 and Mediates Antibody-Dependent Cellular Cytotoxicity
Journal of virology, v 93(24)
15 Dec 2019
PMID: 31554684
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The "closed" conformation of Env is resistant to nonneutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have a limited capacity to inhibit virus infection directly but are able to sensitize viral particles to neutralization by otherwise nonneutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly conserved D368 residue, making them attractive scaffolds for drug development.
HIV-1 has evolved multiple strategies to avoid humoral responses. One efficient mechanism is to keep its envelope glycoprotein (Env) in its "closed" conformation. Here, we report on a new family of small molecules that are able to "open up" Env, thus exposing vulnerable epitopes. This new family of molecules binds in the Phe43 cavity and contacts the highly conserved D368 residue. The structural and biological attributes of molecules of this family make them good candidates for drug development.
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Details
- Title
- A New Family of Small-Molecule CD4-Mimetic Compounds Contacts Highly Conserved Aspartic Acid 368 of HIV-1 gp120 and Mediates Antibody-Dependent Cellular Cytotoxicity
- Creators
- Shilei Ding - Centre Hospitalier de l’Université de MontréalMelissa C Grenier - University of PennsylvaniaWilliam D Tolbert - Uniformed Services University of the Health SciencesDani Vézina - University of MontrealRebekah Sherburn - Uniformed Services University of the Health SciencesJonathan Richard - University of MontrealJérémie Prévost - University of MontrealJean-Philippe Chapleau - University of MontrealGabrielle Gendron-Lepage - Centre Hospitalier de l’Université de MontréalHalima Medjahed - Centre Hospitalier de l’Université de MontréalCameron Abrams - Drexel UniversityJoseph Sodroski - Dana-Farber Cancer InstituteMarzena Pazgier - Uniformed Services University of the Health SciencesAmos B Smith, 3rd - Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA smithab@sas.upenn.edu andres.finzi@umontreal.caAndrés Finzi - Centre Hospitalier de l’Université de Montréal
- Publication Details
- Journal of virology, v 93(24)
- Publisher
- American Society for Microbiology (ASM)
- Grant note
- R01 AI124982 / NIAID NIH HHS P41 GM111244 / NIGMS NIH HHS P01 AI150471 / NIAID NIH HHS U01 AI150741 / NIAID NIH HHS P01 GM056550 / NIGMS NIH HHS R01 AI116274 / NIAID NIH HHS 352417 / CIHR R33 AI129017 / NIAID NIH HHS R01 AI129769 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000499099500014
- Scopus ID
- 2-s2.0-85075613345
- Other Identifier
- 991019168541204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology