Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes

2001 ◽  
Vol 43 (4) ◽  
pp. 455-464 ◽  
Author(s):  
Bhuvaneshwari Mahalingam ◽  
John M. Louis ◽  
Jason Hung ◽  
Robert W. Harrison ◽  
Irene T. Weber
Keyword(s):  
High Resolution ◽  
Crystal Structures ◽  
Drug Resistant ◽  
Substrate Analogue ◽  
Protease Substrate ◽  
Resistant Mutants ◽  
Hiv 1

High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains

2004 ◽  
Vol 338 (2) ◽  
pp. 341-352 ◽  
Author(s):  
Yunfeng Tie ◽  
Peter I. Boross ◽  
Yuan-Fang Wang ◽  
Laquasha Gaddis ◽  
Azhar K. Hussain ◽  
...  
Keyword(s):  
High Resolution ◽  
Crystal Structures ◽  
Peptide Inhibitor ◽  
Drug Resistant ◽  
Clinical Strains ◽  
Hiv 1

scholarly journals Kinetic, Stability, and Structural Changes in High-resolution Crystal Structures of HIV-1 Protease with Drug-resistant Mutations L24I, I50V, and G73S

2005 ◽  
Vol 354 (4) ◽  
pp. 789-800 ◽  
Author(s):  
Fengling Liu ◽  
Peter I. Boross ◽  
Yuan-Fang Wang ◽  
Jozsef Tozser ◽  
John M. Louis ◽  
...  
Keyword(s):  
High Resolution ◽  
Crystal Structures ◽  
Structural Changes ◽  
Kinetic Stability ◽  
Drug Resistant ◽  
Hiv 1

Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection

2000 ◽  
Vol 61 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Catherine Tamalet ◽  
Christophe Pasquier ◽  
Nouara Yahi ◽  
Philippe Colson ◽  
Isabelle Poizot-Martin ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Virological Response ◽  
Drug Resistant ◽  
Resistant Mutants ◽  
Hiv 1

scholarly journals Triumphs of Crystallography in Tackling HIV/AIDS: Drugs by Design

2014 ◽  
Vol 70 (a1) ◽  
pp. C7-C7
Author(s):  
Eddy Arnold
Keyword(s):  
Crystal Structures ◽  
Molecular Mechanisms ◽  
Drug Resistant ◽  
Structure Based Drug Design ◽  
Future Drug ◽  
Support Of Research ◽  
Essential Enzyme ◽  
Aids Drugs ◽  
Rt Inhibitors ◽  
Hiv 1

Crystallography has made extraordinary contributions to our understanding of the biology and chemistry of HIV. Judicious applications of structure-based drug design against HIV-1 protease and reverse transcriptase (RT) has led to the discovery of key drugs that are used in combinations to treat HIV infection. Extensive research and development efforts by pharma, academia, and government have made it possible for an HIV-infected person to live a nearly normal life. I will summarize the elegant structures that have been determined of components of HIV, with an emphasis on the enzyme RT, which my laboratory has studied since 1987. HIV-1 RT is responsible for converting the viral 10-kilobase single-stranded RNA genome to double-stranded DNA. This fascinating and essential enzyme is the target of 13 approved anti-AIDS drugs: 8 nucleoside analog RT inhibitors (NRTIs) and 5 non-nucleoside RT inhibitors (NNRTIs). We have determined crystal structures of wild-type and drug-resistant RTs in complexes with nucleic acid and/or inhibitors. We participated in structure-guided discovery and development of two anti-AIDS drugs with exceptional potency against drug-resistant variants. Crystal structures combined with biochemical data help to elucidate intriguing molecular mechanisms by which HIV-1 develops resistance to different anti-AIDS drugs. Recent crystallographic fragment screening has revealed new allosteric inhibitory binding pockets for future drug discovery. I am very grateful to my many co-workers, colleagues, and friends for their contributions, synchrotron resources at CHESS, BNLS, and APS, and generous funding from NIH in support of research on HIV-1 RT.

scholarly journals Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease†

2007 ◽  
Vol 50 (18) ◽  
pp. 4509-4515 ◽  
Author(s):  
Yuan-Fang Wang ◽  
Yunfeng Tie ◽  
Peter I. Boross ◽  
Jozsef Tozser ◽  
Arun K. Ghosh ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Wild Type ◽  
Antiviral Compound ◽  
Structural Interactions ◽  
Resistant Mutants ◽  
Hiv 1

Slow-, Tight-Binding HIV-1 Reverse Transcriptase Non-Nucleoside Inhibitors Highly Active against Drug-Resistant Mutants

ChemMedChem ◽  
2007 ◽  
Vol 2 (4) ◽  
pp. 445-448 ◽  
Author(s):  
Reynel Cancio ◽  
Antonello Mai ◽  
Dante Rotili ◽  
Marino Artico ◽  
Gianluca Sbardella ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Tight Binding ◽  
Drug Resistant ◽  
Highly Active ◽  
Resistant Mutants ◽  
Nucleoside Inhibitors ◽  
Hiv 1

scholarly journals Mechanism of Substrate Recognition by Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed by a Novel Structural Intermediate

2006 ◽  
Vol 80 (7) ◽  
pp. 3607-3616 ◽  
Author(s):  
Moses Prabu-Jeyabalan ◽  
Ellen A. Nalivaika ◽  
Keith Romano ◽  
Celia A. Schiffer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Crystal Structures ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Structural Model ◽  
Substrate Recognition ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual “intermediate” conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.

scholarly journals An inhibitor-interaction intermediate of HIV-1 protease, revealed by Isothermal Titration Calorimetry and NMR spectroscopy

2018 ◽  
Author(s):  
Shahid N Khan ◽  
John D Persons ◽  
Michel Guerrero ◽  
Tatiana V. Ilina ◽  
Masayuki Oda ◽  
...  
Keyword(s):  
Heat Flow ◽  
Isothermal Titration Calorimetry ◽  
Titration Calorimetry ◽  
Drug Resistant ◽  
Wild Type ◽  
Binding Experiment ◽  
Direct Experiment ◽  
Resistant Mutants ◽  
Inhibitor Interaction ◽  
Hiv 1

AbstractSome of drug-resistant mutants of HIV-1 protease (PR), such as a clinically-relevant drug- resistant PR mutant (Flap+(I54V)) containing L10I, G48V, I54V and V82A mutations, produce significant changes in the balance between entropy and enthalpy of the drug-PR interactions, compared to the wild-type (WT) PR. Here, to gain a comprehensive understanding of the entropy-enthalpy compensation effects, we compared nuclear magnetic resonance (NMR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) data of a WT PR with Flap+(I54V)and related mutants: (1) Flap+(I54V); (2) Flap+(I54A)which evolves from Flap+(I54V)in the continued presence of inhibitor yet does not exhibit entropy-enthalpy compensation; and (3) Flap+(I54), a control mutant that contains only L10I, G48V and V82A mutations. Our data indicate that WT and Flap+(I54A)show enthalpy-driven inhibitor-interaction, while Flap+(I54)and Flap+(I54V)exhibit entropy-driven inhibitor interaction. Interestingly, Flap+(I54A)exhibited significantly slower heat flow in the competitive ITC experiment with a strong binder, darunavir, and a weak binder, acetyl-pepstatin, but did not exhibit such slow heat flow in the direct inhibitor-titration experiments. NMR confirmed replacement of the weak binder by the strong binder in a competitive manner. This difference in the heat flow of the competitive binding experiment compared to the direct experiment can only be explained by assuming an inhibitor-bound intermediate pathway. A similar, but attenuated, tendency for slow heat flow was also detected in the competitive experiment with WT. Overall, our data suggests that an inhibitor-bound intermediate affects the entropy-enthalpy compensation of inhibitor-PR interaction.

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