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

• DOI: 10.1073/pnas.2222073120
• Publication Date: 2023-03-24T18:12:19Z
• Authors: Christopher J. Fr...; Saumya Anang; Zhen Gong; Mohammadjavad Moh...; Jonathan Richard; Catherine Bourassa; Kenny T. Severino; Hannah Richter; Derek Yang; Hung-Ching Chen; Ta-Jung Chiu; Michael S. Seaman; Navid Madani; Cameron Abrams; Andrés Finzi; Wayne A. Hendrickson; Joseph G. Sodroski; Amos B. Smith
• Keywords: Indoline; Trimer; Entry inhibitor

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