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 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.

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 HIV Drug Resistance Mutations in Patients with HIV and HIV-TB Coinfection After Failure of First-Line Therapy: A Prevalence Study in a Resource-Limited Setting

2019 ◽  
Vol 18 ◽  
pp. 232595821984906
Author(s):  
Nawaid Hussain Khan ◽  
Mikashmi Kohli ◽  
Kartik Gupta ◽  
Bimal Kumar Das ◽  
Ravindra Mohan Pandey ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
First Line Therapy ◽  
Resource Limited ◽  
High Prevalence ◽  
Hiv 1 ◽  
Limited Setting

Introduction: The present study aimed to report the prevalent HIV-1 drug-resistant mutations in patients with HIV-1 alone and tuberculosis (TB) coinfection alone to improve our understanding of the mutation patterns and aid treatment decisions. Methods: Patients with HIV-1 and HIV-TB on treatment for more than 1 year with suspected failure were recruited. Sequencing of protease and two-thirds of the region of reverse transcriptase gene was done for drug-resistant mutations. Results: In the HIV-TB group (n = 25), 88%, 92%, and 12% had mutations to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs), respectively. In the HIV-alone group (n = 25), 84%, 100%, and 4% had mutations to NRTIs, NNRTIs, and PIs, respectively. M184V, M41L, D67N, G190A, A98G, and K103N were the most common mutations seen. Conclusion: There is a high prevalence of drug-resistant mutations in HIV and HIV-TB coinfected patients.

scholarly journals L74V increases the reverse transcriptase content of HIV-1 virions with non-nucleoside reverse transcriptase drug-resistant mutations L100I+K103N and K101E+G190S, which results in increased fitness

2013 ◽  
Vol 94 (7) ◽  
pp. 1597-1607 ◽  
Author(s):  
Jiong Wang ◽  
Dongge Li ◽  
Robert A. Bambara ◽  
Hongmei Yang ◽  
Carrie Dykes
Keyword(s):  
Reverse Transcriptase ◽  
Resistance Mutation ◽  
Transcriptase Inhibitor ◽  
Rnase H ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Nnrti Resistance ◽  
Reverse Transcriptase Inhibitor ◽  
Subsequent Addition ◽  
Hiv 1

The fitness of non-nucleoside reverse transcriptase inhibitor (NNRTI) drug-resistant reverse transcriptase (RT) mutants of HIV-1 correlates with the amount of RT in the virions and the RNase H activity of the RT. We wanted to understand the mechanism by which secondary NNRTI-resistance mutations, L100I and K101E, and the nucleoside resistance mutation, L74V, alter the fitness of K103N and G190S viruses. We measured the amount of RT in virions and the polymerization and RNase H activities of mutant RTs compared to wild-type, K103N and G190S. We found that L100I, K101E and L74V did not change the polymerization or RNase H activities of K103N or G190S RTs. However, L100I and K101E reduced the amount of RT in the virions and subsequent addition of L74V restored RT levels back to those of G190S or K103N alone. We conclude that fitness changes caused by L100I, K101E and L74V derive from their effects on RT content.

scholarly journals Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Paul L. Boyer ◽  
Kevin Melody ◽  
Steven J. Smith ◽  
Linda L. Dunn ◽  
Chris Kline ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Hydrophobic Region ◽  
Nnrti Resistance ◽  
Hiv 1

ABSTRACTTwo mutations, G112D and M230I, were selected in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) by a novel nonnucleoside reverse transcriptase inhibitor (NNRTI). G112D is located near the HIV-1 polymerase active site; M230I is located near the hydrophobic region where NNRTIs bind. Thus, M230I could directly interfere with NNRTI binding but G112D could not. Biochemical and virological assays were performed to analyze the effects of these mutations individually and in combination. M230I alone caused a reduction in susceptibility to NNRTIs, while G112D alone did not. The G112D/M230I double mutant was less susceptible to NNRTIs than was M230I alone. In contrast, both mutations affected the ability of RT to incorporate nucleoside analogs. We suggest that the mutations interact with each other via the bound nucleic acid substrate; the nucleic acid forms part of the polymerase active site, which is near G112D. The positioning of the nucleic acid is influenced by its interactions with the “primer grip” region and could be influenced by the M230I mutation.IMPORTANCEAlthough antiretroviral therapy (ART) is highly successful, drug-resistant variants can arise that blunt the efficacy of ART. New inhibitors that are broadly effective against known drug-resistant variants are needed, although such compounds might select for novel resistance mutations that affect the sensitivity of the virus to other compounds. Compound 13 selects for resistance mutations that differ from traditional NNRTI resistance mutations. These mutations cause increased sensitivity to NRTIs, such as AZT.

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.

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