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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-03, Vol.120 (13), p.e2222073120
• Main Authors: Fritschi, Christopher J, Anang, Saumya, Gong, Zhen, Mohammadi, Mohammadjavad, Richard, Jonathan, Bourassa, Catherine, Severino, Kenny T, Richter, Hannah, Yang, Derek, Chen, Hung-Ching, Chiu, Ta-Jung, Seaman, Michael S, Madani, Navid, Abrams, Cameron, Finzi, Andrés, Hendrickson, Wayne A, Sodroski, Joseph G, Smith, 3rd, Amos B
• Format: Article
• Language: English
• Subjects: Antibodies; Antibody-Dependent Cell Cytotoxicity; Antiviral activity; Binding sites; Biological Sciences; CCR5 protein; CD4 antigen; CD4 Antigens - metabolism; CXCR4 protein; Cytotoxicity; Glycoprotein gp120; Glycoprotein gp41; Glycoproteins; HIV; HIV Antibodies - pharmacology; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; HIV-1; Human immunodeficiency virus; Humans; Kinases; Mimetic compounds; Neutralization; Organic chemistry; Scaffolds; Toxicity; Trimers; Vestibules; Virions
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2222073120

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) ] 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.