Benzophenone derivatives of pyrimidines as effective non-nucleoside inhibitors of wild-type and drug-resistant HIV-1 reverse transcriptase

2012 ◽  
Vol 447 (1) ◽  
pp. 280-281 ◽  
Author(s):  
M. M. Prokofjeva ◽  
V. T. Valuev-Elliston ◽  
A. V. Ivanov ◽  
S. N. Kochetkov ◽  
M. S. Novikov ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Wild Type ◽  
Nucleoside Inhibitors ◽  
Derivatives Of ◽  
Hiv 1

scholarly journals High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

2005 ◽  
Vol 49 (11) ◽  
pp. 4546-4554 ◽  
Author(s):  
Reynel Cancio ◽  
Romano Silvestri ◽  
Rino Ragno ◽  
Marino Artico ◽  
Gabriella De Martino ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mechanism Of Action ◽  
Drug Resistant ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

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.

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 Individual Contributions of Mutant Protease and Reverse Transcriptase to Viral Infectivity, Replication, and Protein Maturation of Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1

2001 ◽  
Vol 75 (7) ◽  
pp. 3291-3300 ◽  
Author(s):  
Gabriela Bleiber ◽  
Miguel Munoz ◽  
Angela Ciuffi ◽  
Pascal Meylan ◽  
Amalio Telenti
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Wild Type ◽  
Protein Maturation ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Individual Contributions ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease (PR) and reverse transcriptase (RT) inhibitors may display impaired infectivity and replication capacity. The individual contributions of mutated HIV-1 PR and RT to infectivity, replication, RT activity, and protein maturation (herein referred to as “fitness”) in recombinant viruses were investigated by separately cloning PR, RT, and PR-RT cassettes from drug-resistant mutant viral isolates into the wild-type NL4-3 background. Both mutant PR and RT contributed to measurable deficits in fitness of viral constructs. In peripheral blood mononuclear cells, replication rates (means ± standard deviations) of RT recombinants were 72.5% ± 27.3% and replication rates of PR recombinants were 60.5% ± 33.6% of the rates of NL4-3. PR mutant deficits were enhanced in CEM T cells, with relative replication rates of PR recombinants decreasing to 15.8% ± 23.5% of NL4-3 replication rates. Cloning of the cognate RT improved fitness of some PR mutant clones. For a multidrug-resistant virus transmitted through sexual contact, RT constructs displayed a marked infectivity and replication deficit and diminished packaging of Pol proteins (RT content in virions diminished by 56.3% ± 10.7%, and integrase content diminished by 23.3% ± 18.4%), a novel mechanism for a decreased-fitness phenotype. Despite the identified impairment of recombinant clones, fitness of two of the three drug-resistant isolates was comparable to that of wild-type, susceptible viruses, suggestive of extensive compensation by genomic regions away from PR and RT. Only limited reversion of mutated positions to wild-type amino acids was observed for the native isolates over 100 viral replication cycles in the absence of drug selective pressure. These data underscore the complex relationship between PR and RT adaptive changes and viral evolution in antiretroviral drug-resistant HIV-1.

Sign in / Sign up

Export Citation Format

Share Document