scholarly journals HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

2016 ◽  
Vol 11 (4) ◽  
pp. 1074-1081 ◽  
Author(s):  
Xue Zhi Zhao ◽  
Steven J. Smith ◽  
Daniel P. Maskell ◽  
Mathieu Metifiot ◽  
Valerie E. Pye ◽  
...  
Keyword(s):  
Resistant Mutant ◽  
Drug Resistant ◽  
Strand Transfer ◽  
Integrase Strand Transfer Inhibitors ◽  
Drug Resistant Mutant ◽  
Hiv 1

scholarly journals Molecular modeling of HIV-1 reverse transcriptase drug-resistant mutant strains: implications for the mechanism of polymerase action

1997 ◽  
Vol 10 (12) ◽  
pp. 1379-1383 ◽  
Author(s):  
M. B. Kroeger Smith ◽  
C. J. Michejda ◽  
S. H. Hughes ◽  
P. L. Boyer ◽  
P. A. Janssen ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Reverse Transcriptase ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Mutant Strains ◽  
Drug Resistant Mutant ◽  
Hiv 1

scholarly journals Mechanism of Interaction of Novel Indolylarylsulfone Derivatives with K103N and Y181I Mutant HIV-1 Reverse Transcriptase in Complex with its Substrates

2011 ◽  
Vol 22 (3) ◽  
pp. 107-118 ◽  
Author(s):  
Alberta Samuele ◽  
Sara Bisi ◽  
Alexandra Kataropoulou ◽  
Giuseppe La Regina ◽  
Francesco Piscitelli ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Specific Effects ◽  
Steady State Kinetic ◽  
Drug Resistant Mutant ◽  
K103n Mutation ◽  
New Generation ◽  
Hiv 1

Background: Novel indolylarylsulfones (lASs), designed through rational structure-based molecular modelling and docking approaches, have been recently characterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT). Methods: Here, we studied the interaction of selected halo- and nitra-substituted IAS derivatives, with the RT enzyme carrying the single resistance mutations K103N and Y181I through steady-state kinetic experiments. Results: The studied compounds exhibited high selectivity to the mutant RT in complex with its substrates, behaving as uncompetitive inhibitors. The presence of the K103N mutation, and to a lesser extent the Y181I, stabilized the drug interactions with the viral RT, when both its substrates were bound. Conclusions: The characterization of these mutation-specific effects on inhibitor binding might be relevant to the design of more effective new generation non-nucleoside reverse transcriptase inhibitors, with better resilience towards drug resistant mutants.

scholarly journals Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

2003 ◽  
Vol 77 (2) ◽  
pp. 1306-1315 ◽  
Author(s):  
Moses Prabu-Jeyabalan ◽  
Ellen A. Nalivaika ◽  
Nancy M. King ◽  
Celia A. Schiffer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Protein Ligand Interactions ◽  
Immunodeficiency Virus ◽  
Ligand Interactions ◽  
Drug Resistant Mutant ◽  
Structural Insights ◽  
Hiv 1

ABSTRACT Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

scholarly journals Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance

Biochemistry ◽  
2018 ◽  
Vol 57 (10) ◽  
pp. 1652-1662 ◽  
Author(s):  
Shahid N. Khan ◽  
John D. Persons ◽  
Janet L. Paulsen ◽  
Michel Guerrero ◽  
Celia A. Schiffer ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Structural Changes ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Drug Resistant Mutant ◽  
Hiv 1 ◽  
Nuclear Magnetic

scholarly journals HIV-1 Integrase Inhibitors That Are Broadly Effective against Drug-Resistant Mutants

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Terrence R. Burke ◽  
Stephen H. Hughes
Keyword(s):  
Transfer Reaction ◽  
Drug Resistant ◽  
Strand Transfer ◽  
Integrase Inhibitors ◽  
Integrase Strand Transfer Inhibitors ◽  
Resistant Mutants ◽  
New Compounds ◽  
Susceptibility Profiles ◽  
Dna Substrate ◽  
Hiv 1

ABSTRACT Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients. Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had antiviral profiles against the mutants we tested superior to that of DTG. The susceptibility profiles of 4c and 4d suggest that the compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that are broadly effective in their abilities to inhibit HIV-1 INs with mutations in the active site.

scholarly journals Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

2019 ◽  
Vol 519 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Daniel W. Kneller ◽  
Johnson Agniswamy ◽  
Arun K. Ghosh ◽  
Irene T. Weber
Keyword(s):  
Protease Inhibitor ◽  
Resistant Mutant ◽  
Drug Resistant ◽  
Drug Resistant Mutant ◽  
Hiv 1

scholarly journals Reverse transcriptase backbone can alter the polymerization and RNase activities of non-nucleoside reverse transcriptase mutants K101E+G190S

2013 ◽  
Vol 94 (10) ◽  
pp. 2297-2308
Author(s):  
Jiong Wang ◽  
Dongge Li ◽  
Robert A. Bambara ◽  
Carrie Dykes
Keyword(s):  
Reverse Transcriptase ◽  
Resistant Mutant ◽  
Rnase H ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Virus Growth ◽  
Immunodeficiency Virus ◽  
Drug Resistant Mutant ◽  
Replication Fitness ◽  
Hiv 1

Previous work by our group showed that human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) containing non-nucleoside RT inhibitor (NNRTI) drug resistance mutations has defects in RNase H activity as well as reduced amounts of RT protein in virions. These deficits correlate with replication fitness in the absence of NNRTIs. Viruses with the mutant combination K101E+G190S replicated better in the presence of NNRTIs than in the absence of drug. Stimulation of virus growth by NNRTIs occurred during the early steps of the virus life cycle and was modulated by the RT backbone sequence in which the resistance mutations arose. We wanted to determine what effects RT backbone sequence would have on RT content and polymerization and RNase H activities in the absence of NNRTIs. We compared a NL4-3 RT with K101E+G190S to a patient-isolate RT sequence D10 with K101E+G190S. We show here that, unlike the NL4-3 backbone, the D10 backbone sequence decreased the RNA-dependent DNA polymerization activity of purified recombinant RT compared to WT. In contrast, RTs with the D10 backbone had increased RNase H activity compared to WT and K101E+G190S in the NL4-3 backbone. D10 virions also had increased amounts of RT compared to K101E+G190S in the NL4-3 backbone. We conclude that the backbone sequence of RT can alter the activities of the NNRTI drug-resistant mutant K101E+G190S, and that identification of the amino acids responsible will aid in understanding the mechanism by which NNRTI drug-resistant mutants alter fitness and NNRTIs stimulate HIV-1 virus replication.

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