Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap–Core Interface of HIV-1 Protease

Journal Article · · ACS Omega
 [1];  [1];  [2];  [3];  [1];  [1]
  1. Georgia State Univ., Atlanta, GA (United States)
  2. Georgia State Univ., Atlanta, GA (United States); Univ. of Massachusetts Medical School, Worcester, MA (United States)
  3. Purdue Univ., West Lafayette, IN (United States)
+ Show Author Affiliations
Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best Ki value of 1.9 nM for PRL76V, whereas the other three inhibitors had Ki values of 4.5–7.6 nM, 2–3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PRL76V were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1478117
Journal Information:
ACS Omega, Journal Name: ACS Omega Journal Issue: 9 Vol. 3; ISSN 2470-1343
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (54)

Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site journal March 2016
Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors journal September 2010
Lopinavir/ritonavir resistance in patients infected with HIV-1: two divergent resistance pathways? journal July 2011
Drug resistance mutation profiles of the drug-naïve and first-line regimen-treated HIV-1-infected population of Suzhou, China journal August 2017
Estimating KI values for tight binding inhibitors from dose-response plots journal September 1995
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
Retroviral proteases and their roles in virion maturation journal May 2015
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Thermodynamic Basis of Resistance to HIV-1 Protease Inhibition:  Calorimetric Analysis of the V82F/I84V Active Site Resistant Mutant † journal October 2000
The L76V Drug Resistance Mutation Decreases the Dimer Stability and Rate of Autoprocessing of HIV-1 Protease by Reducing Internal Hydrophobic Contacts journal May 2011
HIV-1 Protease with 20 Mutations Exhibits Extreme Resistance to Clinical Inhibitors through Coordinated Structural Rearrangements journal March 2012
Molecular Dynamics and Free Energy Studies on the Wild-Type and Mutated HIV-1 Protease Complexed with Four Approved Drugs: Mechanism of Binding and Drug Resistance journal June 2009
Drug Resistance Conferred by Mutations Outside the Active Site through Alterations in the Dynamic and Structural Ensemble of HIV-1 Protease journal August 2014
Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring journal March 2012
Tipranavir (PNU-140690):  A Potent, Orally Bioavailable Nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class ∇ journal August 1998
High flavivirus structural plasticity demonstrated by a non-spherical morphological variant journal June 2020
Biosynthesis of a conserved glycolipid anchor for Gram-negative bacterial capsules journal April 2019
Structural basis for substrate binding and catalysis by a self-alkylating ribozyme journal January 2022
HIV-1 resistance rarely observed in subjects using darunavir once-daily regimens across clinical studies journal November 2017
HIV-1 Transmitted Drug Resistance Mutations in Newly Diagnosed Antiretroviral-Naive Patients in Turkey journal January 2016
A short history of SHELX journal December 2007
Conformational flexibility in the flap domains of ligand-free HIV protease journal July 2007
A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex journal July 2003
TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, Shows In Vitro an Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors journal September 2011
Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease journal August 2010
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
GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro journal February 2013
ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease journal December 1998
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
The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage? journal January 2011
Description of the L76V Resistance Protease Mutation in HIV-1 B and “Non-B” Subtypes journal January 2013
HIV-1 Protease, Reverse Transcriptase, and Integrase Variation text January 2016
HIV-1 Protease: Structural Perspectives on Drug Resistance journal December 2009
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
Autocatalytic maturation, physical/chemical properties, and crystal structure of group N HIV-1 protease: Relevance to drug resistance: Characterization of Group N HIV-1 Protease journal September 2010
X-ray crystallographic structure of ABT-378 (Lopinavir) bound to HIV-1 protease journal August 2002
Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20 journal March 2015
Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K journal February 2017
Correlating Conformational Shift Induction with Altered Inhibitor Potency in a Multidrug Resistant HIV-1 Protease Variant journal September 2012
Influence of Flanking Sequences on the Dimer Stability of Human Immunodeficiency Virus Type 1 Protease † journal January 1996
Novel P2 Tris-tetrahydrofuran Group in Antiviral Compound 1 (GRL-0519) Fills the S2 Binding Pocket of Selected Mutants of HIV-1 Protease journal January 2013
Joint X-ray/Neutron Crystallographic Study of HIV-1 Protease with Clinical Inhibitor Amprenavir: Insights for Drug Design journal June 2013
Failure of Treatment with First‐Line Lopinavir Boosted with Ritonavir Can Be Explained by Novel Resistance Pathways with Protease Mutation 76V
  • Nijhuis, Monique; Wensing, Annemarie M. J.; Bierman, Wouter F. W.
  • The Journal of Infectious Diseases, Vol. 200, Issue 5 https://doi.org/10.1086/605329
journal September 2009
Prevalence of darunavir resistance mutations in HIV-1-infected patients failing other protease inhibitors journal July 2007
Phaser crystallographic software journal July 2007
Features and development of Coot journal March 2010
Overview of the CCP 4 suite and current developments journal March 2011
Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial: DRV/r vs . LPV/r over 192 weeks: ARTEMIS journal October 2012
ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease journal December 1998
HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance journal October 2010
HIV-1 Protease, Reverse Transcriptase, and Integrase Variation journal July 2016
Unique Thermodynamic Response of Tipranavir to Human Immunodeficiency Virus Type 1 Protease Drug Resistance Mutations journal May 2007
A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex dataset January 2012
Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics journal December 2016

Cited By (3)

Gag-protease coevolution shapes the outcome of lopinavir-inclusive treatment regimens in chronically infected HIV-1 subtype C patients journal February 2019
Highly drug‐resistant HIV‐1 protease reveals decreased intra‐subunit interactions due to clusters of mutations journal January 2020
Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors journal May 2020

Similar Records

HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics
Journal Article · Wed Aug 31 20:00:00 EDT 2022 · Journal of Molecular Graphics and Modelling · OSTI ID:1887649
The L76V Drug Resistance Mutation Decreases the Dimer Stability and Rate of Autoprocessing of HIV-1 Protease by Reducing Internal Hydrophobic Contacts
Journal Article · Tue Sep 06 00:00:00 EDT 2011 · Biochem. J. · OSTI ID:1020575
Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I
Journal Article · Sat May 11 20:00:00 EDT 2019 · Biochemical and Biophysical Research Communications · OSTI ID:1531006

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
chemical structure
conformation
genetics
inhibitors
noncovalent interactions