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Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation

Journal Article · · European Journal of Medicinal Chemistry
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto University (Japan)
  4. National Center for Global Health and Medicine Research Institute, Tokyo (Japan)
  5. Kumamoto University (Japan); National Center for Global Health and Medicine Research Institute, Tokyo (Japan); National Institutes of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations
Structure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. Here, these inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone atoms in the S2 subsite of HIV-1 protease. Various benzoic acid derivatives have been synthesized and incorporation of these ligands provided potent inhibitors that exhibited subnanomolar level protease inhibitory activity and low nanomolar level antiviral activity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important ligand-binding site interactions for further optimization of this class of protease inhibitors.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Japan Agency for Medical Research and Development (AMED); Japan Society for the Promotion of Science (JSPS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357; W-31109-ENG-38
OSTI ID:
2423428
Journal Information:
European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 255; ISSN 0223-5234
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (56)

Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV journal January 2012
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance journal September 2006
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants journal March 2018
Crystal structures of HIV-1 protease-inhibitor complexes journal August 1993
A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population journal May 2018
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Long-term effects of protease-inhibitor-based combination therapy journal March 2004
Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries journal March 2006
Darunavir en primeras líneas. Estudio TITAN journal October 2008
Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere journal March 1998
Current status and challenges of antiretroviral research and therapy journal January 2010
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV journal December 2007
Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex journal October 2017
Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands journal November 2015
Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia journal November 2008
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains journal April 2004
Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114 journal October 2006
Molecular Analysis of the HIV-1 Resistance Development: Enzymatic Activities, Crystal Structures, and Thermodynamics of Nelfinavir-resistant HIV Protease Mutants journal December 2007
Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies journal April 2020
Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS journal January 2016
Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues journal May 2019
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance journal January 2008
Viracept (Nelfinavir Mesylate, AG1343):  A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease journal November 1997
Synthesis and Wittig reaction of 1-(triphenylphosphoranylidene)-3-methoxy-2-propanone journal January 1981
Nilotinib: A Novel, Selective Tyrosine Kinase Inhibitor journal April 2011
Prevention of HIV-1 Infection with Early Antiretroviral Therapy journal August 2011
Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir journal August 2014
Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization journal July 2007
Expedient Synthesis of N-Substituted 2-Aminothiazoles journal April 1998
The Protein Data Bank journal January 2000
Current and future priorities for the development of optimal HIV drugs journal March 2019
Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients journal January 2009
Phaser crystallographic software journal July 2007
A graphical user interface to the CCP 4 program suite journal June 2003
Coot model-building tools for molecular graphics journal November 2004
Features and development of Coot journal March 2010
Overview of the CCP 4 suite and current developments journal March 2011
JLigand : a graphical tool for the CCP 4 template-restraint library journal March 2012
The CCP4 suite programs for protein crystallography journal September 1994
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
A simple, continuous fluorometric assay for HIV protease journal December 1990
Why do patients fail HIV therapy?: Why do patients fail HIV therapy? journal May 2007
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters: HIV protease mutants altering hydrophobic clusters journal August 2010
Comparison of ATP-Binding Cassette Transporter Interactions with the Tyrosine Kinase Inhibitors Imatinib, Nilotinib, and Dasatinib journal April 2010
Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase journal September 2000
Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro journal September 2003
TMC114, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor Active against Protease Inhibitor-Resistant Viruses, Including a Broad Range of Clinical Isolates journal May 2005
In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors journal September 2010
Mechanism of Darunavir (DRV)’s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance journal May 2018
INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design journal June 1998
The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants journal June 2006
The development of imatinib as a therapeutic agent for chronic myeloid leukemia journal April 2005
Determinants of AIDS and non-AIDS related mortality among people living with HIV in Shiraz, southern Iran: a 20-year retrospective follow-up study journal December 2019
Second generation HIV protease inhibitors against resistant virus journal June 2008
Vital Signs: Deaths Among Persons with Diagnosed HIV Infection, United States, 2010–2018 journal November 2020
Thirty Years of HIV and AIDS: Future Challenges and Opportunities journal June 2011

Figures / Tables (11)

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Related Subjects

60 APPLIED LIFE SCIENCES
Antiviral
Backbone binding
HIV-1 protease inhibitors
Imatinib
Kinase inhibitors
Nilotinib
Pharmacology & Pharmacy
Pyridylpyrimidine
X-ray crystal structure