Crystal Structures of 8-Cl and 9-Cl TIBO Complexed with Wild-type HIV-1 RT and 8-Cl TIBO Complexed with the Tyr181Cys HIV-1 RT Drug-resistant Mutant

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.

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ChemInform Abstract: ZnO-Mediated Regioselective C-Arylsulfonylation of Indoles: A Facile Solvent-Free Synthesis of 2- and 3-Sulfonylindoles and Preliminary Evaluation of Their Activity Against Drug-Resistant Mutant HIV-1 Reverse Transcriptases (RTs).

ChemInform ◽

10.1002/chin.201411086 ◽

2014 ◽

Vol 45 (11) ◽

pp. no-no

Author(s):

Graziella Tocco ◽

Michela Begala ◽

Francesca Esposito ◽

Pierluigi Caboni ◽

Valeria Cannas ◽

...

Keyword(s):

Resistant Mutant ◽

Solvent Free ◽

Preliminary Evaluation ◽

Drug Resistant ◽

Reverse Transcriptases ◽

Drug Resistant Mutant ◽

Solvent Free Synthesis ◽

Hiv 1

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Optimization and Computational Evaluation of a Series of Potential Active Site Inhibitors of the V82F/I84V Drug-resistant Mutant of HIV-1 Protease: an Application of the Relaxed Complex Method of Structure-based Drug Design

Chemical Biology & Drug Design ◽

10.1111/j.1747-0285.2006.00382.x ◽

2006 ◽

Vol 67 (5) ◽

pp. 336-345 ◽

Cited By ~ 17

Author(s):

Alexander L. Perryman ◽

Jung-Hsin Lin ◽

J. Andrew McCammon

Keyword(s):

Drug Design ◽

Active Site ◽

Resistant Mutant ◽

Complex Method ◽

Drug Resistant ◽

Structure Based Drug Design ◽

Computational Evaluation ◽

Drug Resistant Mutant ◽

Hiv 1

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Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Journal of Medicinal Chemistry ◽

10.1021/jm301538e ◽

2013 ◽

Vol 56 (7) ◽

pp. 2804-2812 ◽

Cited By ~ 68

Author(s):

Jizhou Wang ◽

Chunlong Ma ◽

Jun Wang ◽

Hyunil Jo ◽

Belgin Canturk ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Resistant Mutant ◽

Proton Channel ◽

Drug Resistant ◽

Wild Type ◽

Drug Resistant Mutant ◽

Dual Inhibitors ◽

M2 Proton Channel

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

Journal of Virology ◽

10.1128/jvi.77.2.1306-1315.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 1306-1315 ◽

Cited By ~ 61

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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