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Title: Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529

Journal Article · · Nature Chemical Biology
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  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases (NIAID)
  2. Johns Hopkins Univ., Baltimore, MD (United States)
  3. Univ. of Montreal, QC (Canada)
  4. Dana–Farber Cancer Inst., Boston, MA (United States)
  5. Bristol-Myers Squibb, Wallingford, CT (United States)
+ Show Author Affiliations

The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. In this paper, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20–21 hairpin. In both structures, the β20–21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases (NIAID); Intramural AIDS Targeted Antiretroviral Program; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
W-31-109-Eng-38
OSTI ID:
1504988
Journal Information:
Nature Chemical Biology, Vol. 13, Issue 10; ISSN 1552-4450
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 78 works
Citation information provided by
Web of Science

References (62)

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env journal June 2015
Structure and immune recognition of trimeric pre-fusion HIV-1 Env journal October 2014
The HIV-1 Envelope Glycoproteins: Fusogens, Antigens, and Immunogens journal June 1998
Linking Crystallographic Model and Data Quality journal May 2012
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes journal July 2004
Compartmental Absorption Modeling and Site of Absorption Studies to Determine Feasibility of an Extended-Release Formulation of an HIV-1 Attachment Inhibitor Phosphate Ester Prodrug journal June 2013
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody journal September 2012
Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface journal September 2014
Broad neutralization coverage of HIV by multiple highly potent antibodies journal September 2011
A Synthetic Peptide from HIV-1 gp41 Is a Potent Inhibitor of Virus-Mediated Cell—Cell Fusion journal November 1993
Docking and 3D-QSAR studies of BMS-806 analogs as HIV-1 gp120 entry inhibitors journal September 2009
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody journal June 1998
A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies journal September 2013
Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer journal February 2017
A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry journal August 2014
Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068, an Oral HIV-1 Attachment Inhibitor in HIV-1-Infected Subjects journal August 2012
HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug journal May 2012
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 journal July 2010
Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies journal November 2009
Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility journal December 2009
The investigations on HIV-1 gp120 bound with BMS-488043 by using docking and molecular dynamics simulations journal October 2012
Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins journal March 2004
A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding journal August 2003
Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins journal October 2016
Discovery of 4-Benzoyl-1-[(4-methoxy-1 H - pyrrolo[2,3- b ]pyridin-3-yl)oxoacetyl]-2- ( R )-methylpiperazine (BMS-378806):  A Novel HIV-1 Attachment Inhibitor That Interferes with CD4-gp120 Interactions † journal September 2003
Spontaneous Rearrangement of the β20/β21 Strands in Simulations of Unliganded HIV-1 Glycoprotein, gp120 journal September 2012
Global indicators of X-ray data quality journal April 2001
Narrowing the Gap in Life Expectancy Between HIV-Infected and HIV-Uninfected Individuals With Access to Care journal January 2016
Toward the structural genomics of complexes: Crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis journal May 2006
Prediction of the binding mode between BMS-378806 and HIV-1 gp120 by docking and molecular dynamics simulation journal April 2006
Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth journal November 2016
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions journal October 2014
Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068 journal October 2013
CD4-Induced Activation in a Soluble HIV-1 Env Trimer journal July 2014
Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120 journal November 2008
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial journal October 2015
Enfuvirtide: A Review of its Use in the Management of HIV Infection: A Review of its Use in the Management of HIV Infection journal January 2005
Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors journal April 2012
Understanding the binding mode and function of BMS-488043 against HIV-1 viral entry journal April 2011
Homology models of the HIV-1 attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action: BMS-626529, Proposed Mechanism of Action journal December 2014
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
Scorpion-Toxin Mimics of CD4 in Complex with Human Immunodeficiency Virus gp120 journal May 2005
Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 5. An Evolution from Indole to Azaindoles Leading to the Discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1 H -pyrrolo[2,3- c ]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a Drug Candidate That Demonstrates Antiviral Activity in HIV-1-Infected Subjects ∞ journal December 2009
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Combination Antiretroviral Therapy and Recent Declines in AIDS Incidence and Mortality journal March 1999
Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS. journal January 1994
HIV Broadly Neutralizing Antibodies: Taking Good Care Of The 98% journal November 2016
BMS-663068, a safe and effective HIV-1 attachment inhibitor journal October 2015
A stamp on the envelope journal October 2014
Erratum: Corrigendum: Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer journal June 2017
Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy journal January 2007
Prediction of Virological Response and Assessment of Resistance Emergence to the HIV-1 Attachment Inhibitor BMS-626529 During 8-Day Monotherapy With Its Prodrug BMS-663068 journal January 2013
The CCP4 suite programs for protein crystallography journal September 1994
In Vitro Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068 journal April 2012
In Vivo Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043 journal November 2010
Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity journal October 2005
Biochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions journal September 2003
Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155 journal March 2004
Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies journal July 2005
Envelope Conformational Changes Induced by Human Immunodeficiency Virus Type 1 Attachment Inhibitors Prevent CD4 Binding and Downstream Entry Events journal March 2006
PHENIX: a comprehensive Python-based system for macromolecular structure solution. text January 2010

Cited By (14)

The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions journal October 2017
Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry journal January 2019
Capturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide journal February 2019
A sequestered fusion peptide in the structure of an HIV-1 transmitted founder envelope trimer journal February 2019
Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements journal January 2020
Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET journal April 2019
Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV journal December 2018
The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review journal October 2019
Concomitant Enhancement of HIV-1 Replication Potential and Neutralization-Resistance in Concert With Three Adaptive Mutations in Env V1/C2/C4 Domains journal January 2019
Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency journal August 2018
Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor journal April 2019
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations journal March 2018
Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency journal January 2019
Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation journal December 2018

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