The processivity of DNA synthesis exhibited by drug-resistant variants of human immunodeficiency virus type-1 reverse transcriptase

ABSTRACT Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

Download Full-text

De NovoParallel Design, Synthesis and Evaluation of Inhibitors against the Reverse Transcriptase of Human Immunodeficiency Virus Type-1 and Drug-Resistant Variants

Journal of Medicinal Chemistry ◽

10.1021/jm0613121 ◽

2007 ◽

Vol 50 (10) ◽

pp. 2370-2384 ◽

Cited By ~ 25

Author(s):

Alon Herschhorn ◽

Lena Lerman ◽

Michal Weitman ◽

Iris Oz Gleenberg ◽

Abraham Nudelman ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Drug Resistant ◽

Design Synthesis ◽

Immunodeficiency Virus

Download Full-text

Mutations in the Primer Grip of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Impair Proviral DNA Synthesis and Virion Maturation

Journal of Virology ◽

10.1128/jvi.72.9.7676-7680.1998 ◽

1998 ◽

Vol 72 (9) ◽

pp. 7676-7680 ◽

Cited By ~ 25

Author(s):

Qiang Yu ◽

Michele Ottmann ◽

Christine Pechoux ◽

Stuart Le Grice ◽

Jean-Luc Darlix

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Dna Synthesis ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Virus Assembly ◽

Conserved Residues ◽

Proviral Dna ◽

Immunodeficiency Virus

ABSTRACT This report describes the effects of mutating highly conserved residues in the primer grip domain of human immunodeficiency virus type 1 reverse transcriptase (RT) on virus formation and infectivity. Among a series of RT mutant viruses, three (M230A, L234D, and W239A) were found to be noninfectious or very poorly infectious. Our data indicate that these mutations in RT caused severe defects in proviral DNA synthesis. Interestingly, assembly and maturation of mutant virus M230A were similar to those of the wild type, while mutants L234D and W239A showed impaired maturation. The immature morphology of RT mutants L234D and W239A is due at least in part to premature cleavage of the gag-pol precursor, prior to virion budding, indicating that intracellular stability of Pr160 gag-pol is of key importance during virus assembly.

Download Full-text