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Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir
K. Grantz Šašková, M. Kožíšek, P. Řezáčová, J. Brynda, T. Yashina, R.M. Kagan, J. Konvalinka
Jazyk angličtina Země Spojené státy americké
Typ dokumentu práce podpořená grantem
E-zdroje NLK
Free Medical Journals od 1967 do Před 6 měsíciFreely Accessible Science Journals od 1967 do Před 6 měsíci
PubMed Central od 1967 do Před 6 měsíci
Europe PubMed Central od 1967 do Před 6 měsíci
Open Access Digital Library od 1967-02-01
Open Access Digital Library od 1967-02-01
- MeSH
- genové produkty env - virus lidské imunodeficience metabolismus MeSH
- genové produkty gag - virus lidské imunodeficience metabolismus MeSH
- HIV infekce virologie MeSH
- HIV-1 izolace a purifikace účinky léků MeSH
- HIV-proteasa genetika chemie metabolismus MeSH
- inhibitory HIV-proteasy farmakologie MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- missense mutace MeSH
- molekulární modely MeSH
- molekulární sekvence - údaje MeSH
- mutační analýza DNA MeSH
- polyproteiny metabolismus MeSH
- sekvence aminokyselin MeSH
- substituce aminokyselin MeSH
- sulfonamidy farmakologie MeSH
- terciární struktura proteinů MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- virová léková rezistence MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.
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- $a Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.
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