Journal article
Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v 120(13), e2222073120
28 Mar 2023
PMID: 36961924
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale con-formational 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 var-iants 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 pi-pi 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.
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Details
- Title
- Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity
- Publication Details
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v 120(13), e2222073120
- Publisher
- NATL ACAD SCIENCES; WASHINGTON
- Grant note
- We thank Irwin Chaiken and other project leaders of the P01 Consortium Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry (NIH Grant No. AI 150471) . We also thank the staff at Northeastern Collaborative Access Team (NE-CAT) beamlines at Advanced Photon Source (APS) for their support during data collection. We also acknowledge Dr. Charles Ross and Dr. Jun Gu (University of Pennsylvania) for their assistance in obtaining mass and NMR spectra, respectively. We also thank Dr. Mark Hogarth for kindly providing recombinant dimeric Fc?RIIIa and Dr Beatrice Hahn for providing the follow- ing infectious molecular clones: HIV CH77TF , HIV CH185TF , HIV CH850TF , and HIV CH167 . A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001001368800001
- Scopus ID
- 2-s2.0-85151044860
- Other Identifier
- 991021861291704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology