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

Publication Type:

Journal Article

Source:

Proc Natl Acad Sci U S A, Volume 120, Issue 13, p.e2222073120 (2023)

Keywords:

Antibody-Dependent Cell Cytotoxicity, CD4 Antigens, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV Seropositivity, HIV-1, Humans

Abstract:

<p>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 &quot;open,&quot; 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.</p>

PDB: 
8FLY for BNM-III-170 (53), 8FLZ for CJF-III-049-S (54), 8FM0 for CJF-III-214 (55), 8FM2 for CJF-III-289 (56), 8FM3 for CJF-III-288 (57), 8FM4 for CJF-IV-047 (58), 8FM5 for DY-III-065 (59), 8FM7 for CJF-III-192 (60), and 8FM8 for CJF-IV-046 (61)
Detector: 
EIGER
EIGER2
Beamline: 
24-ID-C
24-ID-E