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
  • 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.
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