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Title: Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions. Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies

Journal Article · · J. Med. Chem.
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. (Japan); National Center for Global Health and Medicine, Tokyo (Japan)
  4. Kumamoto Health Science Univ. (Japan)
+ Show Author Affiliations

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand–binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand–binding site interactions are possibly responsible for their potent activity.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1222022
Journal Information:
J. Med. Chem., Vol. 58, Issue 17
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 12 works
Citation information provided by
Web of Science

References (41)

Strategies for antiviral therapy in AIDS journal February 1987
Active human immunodeficiency virus protease is required for viral infectivity. journal July 1988
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
Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries journal March 2006
Current status and challenges of antiretroviral research and therapy journal January 2010
Why do patients fail HIV therapy?: Why do patients fail HIV therapy? journal May 2007
Principles and practice of HIV-protease inhibitor pharmacoenhancement: HIV-protease inhibitor pharmacoenhancement journal April 2001
Mortality and progression to AIDS after starting highly active antiretroviral therapy journal January 2003
Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults journal December 1999
Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance journal January 2010
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance journal September 2006
Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance journal August 2006
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
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
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
Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV journal January 2012
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance journal January 2008
Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors journal January 2011
Design of gem -Difluoro- bis -Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation journal October 2014
GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration journal September 2013
Synthesis of 1,2- O -Isopropylidene-L-threitol and its Conversion to ( R )-1,2- O -Isopropylideneglycerol journal January 1985
Cesium promoted O-alkylation of alcohols for the efficient ether synthesis journal March 1999
Asymmetric Induction in the [2,3] Wittig Rearrangement by Chiral Substituents in the Allyl Moiety journal February 1988
Asymmetric Induction and Simple Diastereoselectivity in the [2,3] Wittig Rearrangement of Ester Enolates journal April 1989
Mitsunobu and Related Reactions: Advances and Applications journal June 2009
A Convergent Synthesis of (+)-Cryptophycin B, a Potent Antitumor Macrolide from Nostoc sp. Cyanobacteria journal June 2000
A simple, continuous fluorometric assay for HIV protease journal December 1990
The role of dolutegravir in the management of HIV infections journal February 2015
Prevalence of Darunavir Resistance–Associated Mutations: Patterns of Occurrence and Association with Past Treatment journal October 2007
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
Amino Acid Substitutions in Gag Protein at Non-cleavage Sites Are Indispensable for the Development of a High Multitude of HIV-1 Resistance against Protease Inhibitors journal February 2002
Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1 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
Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes journal January 2001
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters: HIV protease mutants altering hydrophobic clusters journal August 2010
Phaser crystallographic software journal July 2007
Overview of the CCP 4 suite and current developments journal March 2011
A graphical user interface to the CCP 4 program suite journal June 2003
Features and development of Coot journal March 2010
PRODRG : a tool for high-throughput crystallography of protein–ligand complexes journal July 2004

Cited By (2)

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors journal June 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

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