Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity

  • ACS Med Chem Lett. 2024 Oct 28;15(11):1961-1969. doi: 10.1021/acsmedchemlett.4c00403.
Daniel Lee  1 ,  Ling Niu  2 ,  Shilei Ding  3 ,  Huile Zhu  1 ,  William D Tolbert  2 ,  Halima Medjahed  3 ,  Guillaume Beaudoin-Bussières  3  4 ,  Cameron Abrams  5 ,  Andrés Finzi  3  4 ,  Marzena Pazgier  2 ,  Amos B Smith 3rd  1
Affiliations
  • 1. Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 2. Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, United States.
  • 3. Centre de Recherche du CHUM, Montréal, Quebec H2X 0A9, Canada.
  • 4. Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.
  • 5. Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.
PMID: 39563795 DOI: 10.1021/acsmedchemlett.4c00403
Abstract

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β20-21 loop and the α1-helix lead to improved Antiviral activity.

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