skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

Journal Article · · Journal of Medicinal Chemistry
ORCiD logo [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [4];  [5];  [5]; ORCiD logo [4];  [6]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); Kumamoto Health Science Univ. (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
  3. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
  4. Georgia State Univ., Atlanta, GA (United States)
  5. National Inst. of Health (NIH), Bethesda, MD (United States)
  6. Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
+ Show Author Affiliations

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Furthermore, two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; Intramural Research Program of the Center for Cancer Research; National Cancer Inst.
Grant/Contract Number:
GM53386; GM62920; W-31-109-Eng-38
OSTI ID:
1368286
Journal Information:
Journal of Medicinal Chemistry, Vol. 60, Issue 10; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 54 works
Citation information provided by
Web of Science

References (38)

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS journal January 2016
The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study journal June 2011
Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study journal August 2010
Improved survival in HIV-infected persons: consequences and perspectives journal July 2007
Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naive Individuals journal January 2009
HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment journal March 2016
Current status and challenges of antiretroviral research and therapy journal January 2010
Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV journal January 2012
Darunavir, a New PI with Dual Mechanism: From a Novel Drug Design Concept to New Hope against Drug-Resistant HIV book January 2010
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance journal January 2008
Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance journal August 2006
Crystal Structures of the Inactive D30N Mutant of Feline Immunodeficiency Virus Protease Complexed with a Substrate and an Inhibitor † , ‡ journal September 1997
HIV-1 Protease: Structural Perspectives on Drug Resistance journal December 2009
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance journal September 2006
Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere journal March 1998
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV journal December 2007
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
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
Structural and Thermodynamic Basis for the Binding of TMC114, a Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor journal October 2004
A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site journal February 2002
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
Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114 journal October 2006
Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P 2 Ligands: Structure−Activity Studies and Biological Evaluation journal January 2011
Biological Aspects of Emerging Benzothiazoles: A Short Review journal January 2013
A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles journal October 2015
[4 + 2] Cycloaddition Reactions Catalyzed by a Chiral Oxazaborolidinium Cation. Reaction Rates and Diastereo-, Regio-, and Enantioselectivity Depend on Whether Both Bonds Are Formed Simultaneously journal February 2010
Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions journal February 2016
Copper-catalyzed addition of diboron reagents to α,β-acetylenic esters: efficient synthesis of β-boryl-α,β-ethylenic esters journal January 2008
An Expedient Procedure for the Oxidative Cleavage of Olefinic Bonds with PhI(OAc) 2 , NMO, and Catalytic OsO 4 journal February 2010
Design and Synthesis of Stereochemically Defined Novel Spirocyclic P2-Ligands for HIV-1 Protease Inhibitors journal October 2008
Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure journal August 2011
The first practical method for asymmetric epoxidation journal August 1980
Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization journal September 1987
Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1–P2 ligands journal January 2014
Sixty years of staudinger reaction journal January 1981
A simple, continuous fluorometric assay for HIV protease journal December 1990
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
GRL-02031, a Novel Nonpeptidic Protease Inhibitor (PI) Containing a Stereochemically Defined Fused Cyclopentanyltetrahydrofuran Potent against Multi-PI-Resistant Human Immunodeficiency Virus Type 1 In Vitro journal October 2008

Cited By (12)

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors journal June 2018
Asymmetric Diels–Alder reaction of 3-(acyloxy)acryloyl oxazolidinones: optically active synthesis of a high-affinity ligand for potent HIV-1 protease inhibitors journal January 2019
Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified journal March 2018
Gold(I)‐Catalyzed Cycloisomerization of 3‐Alkoxyl‐1,6‐diynes: A Facile Access to Bicyclo[2.2.1]hept‐5‐en‐2‐ones journal March 2020
Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening journal May 2019
Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen journal January 2019
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
Novel Protease Inhibitors Containing C-5-Modified bis -Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance journal May 2019
Ligand-controlled palladium catalysis enables switch between mono- and di-arylation of primary aromatic amines with 2-halobenzothiazoles journal January 2020
Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies journal October 2019
A Structural View on Medicinal Chemistry Strategies against Drug Resistance journal January 2019
Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified text January 2018

Similar Records

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 Article · Tue Feb 13 00:00:00 EST 2018 · ChemMedChem · OSTI ID:1368286
+10 more
Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X-ray Structural Analysis
Journal Article · Tue May 15 00:00:00 EDT 2018 · Journal of Medicinal Chemistry · OSTI ID:1368286
+9 more
GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro
Journal Article · Mon Sep 25 00:00:00 EDT 2017 · Scientific Reports · OSTI ID:1368286
+5 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Antimicrobial agents
Peptides and proteins
Ligands
Inhibitors
Noncovalent interactions