2. Academic Validation
  3. Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity

Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity

  • Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2222073120. doi: 10.1073/pnas.2222073120.
Christopher J Fritschi 1,  Saumya Anang 2 3,  Zhen Gong 4,  Mohammadjavad Mohammadi 5,  Jonathan Richard 6 7,  Catherine Bourassa 7,  Kenny T Severino 8,  Hannah Richter 8,  Derek Yang 1,  Hung-Ching Chen 1,  Ta-Jung Chiu 1,  Michael S Seaman 8,  Navid Madani 2 3,  Cameron Abrams 5,  Andrés Finzi 6 7,  Wayne A Hendrickson 4 9,  Joseph G Sodroski 2 3 10,  Amos B Smith 3rd 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104.
  • 2 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
  • 3 Department of Microbiology, Harvard Medical School, Boston, MA 02115.
  • 4 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.
  • 5 Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104.
  • 6 Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada.
  • 7 Departement de Microbiologie, Infectiologie et Immunologie, Universite de Montreal, Montreal, QC H3T 1J4, Canada.
  • 8 Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215.
  • 9 Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032.
  • 10 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115.
PMID: 36961924 DOI: 10.1073/pnas.2222073120
Abstract

Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by Antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in Antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 Infection.

Keywords

antibody-dependent cellular cytotoxicity; antiretroviral therapy; entry inhibitor; gp120; structure-based drug design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-Y0788
    99.89%, Indole Derivative
    HIV