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Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies

Journal Article · · Bioorganic and Medicinal Chemistry Letters
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. National Center for Global Health and Medicine, Tokyo (Japan); Kumamoto University (Japan)
  4. National Center for Global Health and Medicine, Tokyo (Japan); National Cancer Institute, Bethesda, MD (United States); Kumamoto University Hospital (Japan)
+ Show Author Affiliations
Here, we report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Japan Agency for Medical Research and Development (AMED); 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:
2423424
Journal Information:
Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: C Vol. 83; ISSN 0960-894X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (32)

Darunavir, a New PI with Dual Mechanism: From a Novel Drug Design Concept to New Hope against Drug-Resistant HIV book January 2010
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
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
Design of the anti-HIV protease inhibitor darunavir book January 2013
Darunavir en primeras líneas. Estudio TITAN journal October 2008
Discovery of a new flavin N5-adduct in a tyrosine to phenylalanine variant of d-Arginine dehydrogenase journal January 2022
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
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
Synthesis of amide derivatives for electron deficient amines and functionalized carboxylic acids using EDC and DMAP and a catalytic amount of HOBt as the coupling reagents journal January 2021
Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS journal January 2016
Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance journal January 2008
Capturing the Reaction Pathway in Near-Atomic-Resolution Crystal Structures of HIV-1 Protease journal September 2012
Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid journal October 2018
Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance journal January 2022
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
Darunavir for the treatment of HIV infection journal June 2018
Prevalence of Darunavir Resistance–Associated Mutations: Patterns of Occurrence and Association with Past Treatment journal October 2007
Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients journal January 2009
A simple, continuous fluorometric assay for HIV protease journal December 1990
P2′ Benzene Carboxylic Acid Moiety Is Associated with Decrease in Cellular Uptake: Evaluation of Novel Nonpeptidic HIV-1 Protease Inhibitors Containing P2 bis -Tetrahydrofuran Moiety journal July 2013
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
Rational Approach to AIDS Drug Design Through Structural Biology journal February 2002
HIV-1 Antiretroviral Resistance: Scientific Principles and Clinical Applications journal January 2012
Thirty Years of HIV and AIDS: Future Challenges and Opportunities journal June 2011

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59 BASIC BIOLOGICAL SCIENCES
Chemistry
Darunavir
HIV-1 protease
Inhibitor
Pharmacology & Pharmacy
Synthesis
X-ray structure