Abstract |
Subtype F wild type HIV protease has been kinetically characterized using six commercial inhibitors ( amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) commonly used for HIV/ AIDS treatment, as well as inhibitor TL-3 and acetyl-pepstatin. We also obtained kinetic parameters for two multi-resistant proteases (one of subtype B and one of subtype F) harboring primary and secondary mutations selected by intensive treatment with ritonavir/ nelfinavir. This newly obtained biochemical data shows that all six studied commercially available protease inhibitors are significantly less effective against subtype F HIV proteases than against HIV proteases of subtype B, as judged by increased K(i) and biochemical fitness (vitality) values. Comparison with previously reported kinetic values for subtype A and C HIV proteases show that subtype F wild type proteases are significantly less susceptible to inhibition. These results demonstrate that the accumulation of natural polymorphisms in subtype F proteases yields catalytically more active enzymes with a large degree of cross-resistance, which thus results in strong virus viability.
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Authors | Sandra Krauchenco, Nadia H Martins, Mario Sanches, Igor Polikarpov |
Journal | Journal of enzyme inhibition and medicinal chemistry
(J Enzyme Inhib Med Chem)
Vol. 24
Issue 3
Pg. 638-45
(Jun 2009)
ISSN: 1475-6374 [Electronic] England |
PMID | 18825538
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- HIV Protease Inhibitors
- HIV Protease
- Nelfinavir
- Ritonavir
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Topics |
- Amino Acid Sequence
- Binding Sites
- Drug Resistance, Viral
- Enzyme Activation
(drug effects)
- HIV
(drug effects, enzymology, genetics)
- HIV Infections
(drug therapy, genetics, virology)
- HIV Protease
(chemistry, classification, genetics, metabolism)
- HIV Protease Inhibitors
(classification, pharmacology, therapeutic use)
- Humans
- Kinetics
- Microbial Viability
(drug effects, genetics)
- Molecular Sequence Data
- Mutation
- Nelfinavir
(pharmacology)
- Polymorphism, Genetic
- Ritonavir
(pharmacology)
- Sequence Alignment
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