Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Characterization of a Novel CD4 Mimetic Compound YIR-821 against HIV-1 Clinical Isolates

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/jvi.01638-22· OSTI ID:2423890
 [1];  [1];  [2];  [3];  [3];  [3];  [4];  [1];  [1];  [1];  [5];  [5];  [5];  [6];  [2];  [3];  [1]
  1. Kumamoto University (Japan)
  2. Uniformed Services University of the Health Sciences, Bethesda, MD (United States)
  3. Centre de Recherche du CHUM (CRCHUM), Montreal, QC (Canada); Univ. of Montreal, QC (Canada)
  4. National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka (Japan)
  5. Tokyo Medical and Dental University (Japan)
  6. Univ. of Pennsylvania, Philadelphia, PA (United States)
+ Show Author Affiliations
Small CD4-mimetic compound (CD4mc), which inhibits the interaction between gp120 with CD4, acts as an entry inhibitor and induces structural changes in the HIV-1 envelope glycoprotein trimer (Env) through its insertion within the Phe43 cavity of gp120. Here, we recently developed YIR-821, a novel CD4mc, that has potent antiviral activity and lower toxicity than the prototype NBD-556. To assess the possibility of clinical application of YIR-821, we tested its antiviral activity using a panel of HIV-1 pseudoviruses from different subtypes. YIR-821 displayed entry inhibitor activity against 53.5% (21/40) of the pseudoviruses tested and enhanced neutralization mediated by coreceptor binding site (CoRBS) antibodies in 50% (16/32) of these. Furthermore, when we assessed the antiviral effects using a panel of pseudoviruses and autologous plasma IgG, enhancement of antibody-mediated neutralization activity was observed for 48% (15/31) of subtype B strains and 51% (28/55) of non-B strains. The direct antiviral activity of YIR-821 as an entry inhibitor was observed in 53% of both subtype B (27/51) and non-B subtype (40/75) pseudoviruses. Enhancement of antibody-dependent cellular cytotoxicity was also observed with YIR-821 for all six selected clinical isolates, as well as for the transmitted/founder (T/F) CH58 virus-infected cells. The sequence diversity in the CD4 binding site as well as other regions, such as the gp120 inner domain layers or gp41, may be involved in the multiple mechanisms related to the sensitive/resistant phenotype of the virus to YIR-821. Our findings may facilitate the clinical application of YIR-821.
Research Organization:
SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
Canadian Institute of Health Research Foundation (CIHR); Canadian Research Chair for Retroviral Entry; Japan Agency for Medical Research and Development (AMED); Japan Science and Technology Agency (JST); Japan Society for the Promotion of Science (JSPS) KAKENHI; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
2423890
Journal Information:
Journal of Virology, Journal Name: Journal of Virology Journal Issue: 1 Vol. 97; ISSN 0022-538X; ISSN 1098-5514
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
English

References (49)

Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors journal February 2016
Measuring HIV Neutralization in a Luciferase Reporter Gene Assay book January 2009
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses journal January 2019
Small molecular CD4 mimics as HIV entry inhibitors journal November 2011
CD4 mimics as HIV entry inhibitors: Lead optimization studies of the aromatic substituents journal May 2013
A CD4 mimic as an HIV entry inhibitor: Pharmacokinetics journal December 2013
Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors journal February 2022
CD4 mimics targeting the mechanism of HIV entry journal January 2010
A minimally cytotoxic CD4 mimic as an HIV entry inhibitor journal January 2016
An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity journal April 2019
Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir journal June 2021
Functional T cell subsets contribute differentially to HIV peptide-specific responses within infected individuals: Correlation of these functional T cell subsets with markers of disease progression journal July 2007
Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins journal October 2016
Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region journal May 2016
Impact of HIV-1 Envelope Conformation on ADCC Responses journal April 2018
Identification of N-phenyl-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4 journal September 2005
Replication competent molecular clones of HIV-1 expressing Renilla luciferase facilitate the analysis of antibody inhibition in PBMC journal December 2010
Complementary and synergistic activities of anti-V3, CD4bs and CD4i antibodies derived from a single individual can cover a wide range of HIV-1 strains journal January 2015
Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors journal January 2021
Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition journal January 2016
Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding journal December 2012
CD4 mimetics sensitize HIV-1-infected cells to ADCC journal May 2015
High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. journal September 1990
Emergence of Autologous Neutralization‐Resistant Variants from Preexisting Human Immunodeficiency Virus (HIV) Quasi Species during Virus Rebound in HIV Type 1–Infected Patients Undergoing Highly Active Antiretroviral Therapy journal March 2002
HIV Infection Affects Blood Myeloid Dendritic Cells after Successful Therapy and despite Nonprogressing Clinical Disease journal April 2009
The V1/V2 Region of Human Immunodeficiency Virus Type 1 Modulates the Sensitivity to Neutralization by Soluble CD4 and Cellular Tropism journal October 1997
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes journal July 2004
Opening the HIV envelope: potential of CD4 mimics as multifunctional HIV entry inhibitors journal September 2020
Generation of a replication-competent simian–human immunodeficiency virus, the neutralization sensitivity of which can be enhanced in the presence of a small-molecule CD4 mimic journal December 2013
Coot model-building tools for molecular graphics journal November 2004
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
The CCP4 suite programs for protein crystallography journal September 1994
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions journal October 2014
Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies journal January 2016
A Novel Assay for Antibody-Dependent Cell-Mediated Cytotoxicity against HIV-1- or SIV-Infected Cells Reveals Incomplete Overlap with Antibodies Measured by Neutralization and Binding Assays journal November 2012
Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells journal November 2018
Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds journal February 2017
Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors journal December 2016
Receptor-Ligand Requirements for Increased NK Cell Polyfunctional Potential in Slow Progressors Infected with HIV-1 Coexpressing KIR3DL1*h/*y and HLA-B*57 journal June 2011
Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding. journal January 1993
Characterization of Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Variants Selected for Resistance to a CD4-Mimetic Compound journal September 2022
The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site journal June 2020
High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans journal January 2011
M48U1 CD4 mimetic has a sustained inhibitory effect on cell-associated HIV-1 by attenuating virion infectivity through gp120 shedding journal February 2013
Unique binding modes for the broad neutralizing activity of single-chain variable fragments (scFv) targeting CD4-induced epitopes journal September 2017
Functional analysis of a monoclonal antibody reactive against the C1C2 of Env obtained from a patient infected with HIV-1 CRF02_AG journal August 2021
Soluble CD4 and CD4-Mimetic Compounds Inhibit HIV-1 Infection by Induction of a Short-Lived Activated State journal April 2009
Phenotypic and Genotypic Co-receptor Tropism Testing in HIV-1 Epidemic Region of Tanzania Where Multiple Non-B Subtypes Co-circulate journal July 2021

Similar Records

Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies
Journal Article · Fri Sep 07 00:00:00 EDT 2012 · Biochemical and Biophysical Research Communications · OSTI ID:22210242
Identification of a D-amino acid decapeptide HIV-1 entry inhibitor
Journal Article · Fri Sep 08 00:00:00 EDT 2006 · Biochemical and Biophysical Research Communications · OSTI ID:20854447
Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation
Journal Article · Sun Mar 28 20:00:00 EDT 2021 · Nature Communications · OSTI ID:1816554

Related Subjects

60 APPLIED LIFE SCIENCES
ADCC
CD4mc
CD4mimic
HIV-1
Virology
clinical strain
conformation
entry inhibition
envelope
envelope conformation
monoclonal antibody
mutation
neutralization
non-B subtypes
non-subtype B
plasma IgG
subtype B