Changes in HIV-1 Protease-Inhibitor Interaction Due to Amino Acids Polymorphisms and Drug-Pressure Selected Mutations

ABSTRACT We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 μM). UIC-94003 was also potent against multi-PI-resistant HIV-1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 μM). Upon selection of HIV-1 in the presence of UIC-94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and wide-spectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1.

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Characterization of HIV-1 Protease-Inhibitor Interaction by Interflap Distance Measurement, NMR Spectroscopy, and Solution Kinetics

Biophysical Journal ◽

10.1016/j.bpj.2008.12.260 ◽

2009 ◽

Vol 96 (3) ◽

pp. 70a

Author(s):

Angelo M. Veloro ◽

Mandy E. Blackburn ◽

Luis Galiano ◽

Gail E. Fanucci

Keyword(s):

Nmr Spectroscopy ◽

Protease Inhibitor ◽

Distance Measurement ◽

Solution Kinetics ◽

Inhibitor Interaction ◽

Hiv 1

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Gp41 and Gag amino acids linked to HIV-1 protease inhibitor-based second-line failure in HIV-1 subtype A from Western Kenya

Journal of the International AIDS Society ◽

10.1002/jia2.25024 ◽

2017 ◽

Vol 20 (3) ◽

pp. e25024 ◽

Cited By ~ 8

Author(s):

Mia Coetzer ◽

Lauren Ledingham ◽

Lameck Diero ◽

Emmanuel Kemboi ◽

Millicent Orido ◽

...

Keyword(s):

Amino Acids ◽

Protease Inhibitor ◽

Second Line ◽

Western Kenya ◽

Subtype A ◽

Hiv 1

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High Sequence Conservation of Human Immunodeficiency Virus Type 1 Reverse Transcriptase under Drug Pressure despite the Continuous Appearance of Mutations

Journal of Virology ◽

10.1128/jvi.79.16.10718-10729.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10718-10729 ◽

Cited By ~ 42

Author(s):

Francesca Ceccherini-Silberstein ◽

Federico Gago ◽

Maria Santoro ◽

Caterina Gori ◽

Valentina Svicher ◽

...

Keyword(s):

Amino Acids ◽

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Sequence Conservation ◽

Drug Pressure ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT To define the extent of sequence conservation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in vivo, the first 320 amino acids of RT obtained from 2,236 plasma-derived samples from a well-defined cohort of 1,704 HIV-1-infected individuals (457 drug naïve and 1,247 drug treated) were analyzed and examined in structural terms. In naïve patients, 233 out of these 320 residues (73%) were conserved (<1% variability). The majority of invariant amino acids clustered into defined regions comprising between 5 and 29 consecutive residues. Of the nine longest invariant regions identified, some contained residues and domains critical for enzyme stability and function. In patients treated with RT inhibitors, despite profound drug pressure and the appearance of mutations primarily associated with resistance, 202 amino acids (63%) remained highly conserved and appeared mostly distributed in regions of variable length. This finding suggests that participation of consecutive residues in structural domains is strictly required for cooperative functions and sustainability of HIV-1 RT activity. Besides confirming the conservation of amino acids that are already known to be important for catalytic activity, stability of the heterodimer interface, and/or primer/template binding, the other 62 new invariable residues are now identified and mapped onto the three-dimensional structure of the enzyme. This new knowledge could be of help in the structure-based design of novel resistance-evading drugs.

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