Characterisation of Mutated Proteinases Derived from HIV-Positive Patients: Enzyme Activity, Vitality and Inhibition

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Title:Characterisation of Mutated Proteinases Derived from HIV-Positive Patients: Enzyme Activity, Vitality and Inhibition
Creators:
Kožíšek, Milan
Prejdová, Jana
Souček, Milan
Machala, Ladislav
Staňková, Marie
Linka, Marek
Brůčková, Marie
Konvalinka, Jan
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 69, 3, pp. 703-714
Uncontrolled Keywords:HIV protease, Enzyme kinetics, Peptidomimetics, Viral resistance, Pseudopeptides, Enzyme inhibitors, AIDS, Antiviral drugs, Aspartic proteases

Abstract

HIV protease (PR) specifically cleaves viral polyproteins to yield infectious progeny virus particles. Inactivation of PR leads to loss of virus infectivity and PR thus became an attractive pharmaceutic target. Indeed, seven protease inhibitors (PI) have been approved for clinical use to date. However, emerging resistant viral variants with reduced sensitivity to PIs become a major obstacle to successful control of viral replication. We have previously reported the design, testing and structural analysis of a pseudopeptide inhibitor, QF34, which efficiently inhibits a wide variety of PR variants. In a clinical study, we have monitored more than 100 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy including PI. In this paper we describe kinetic characterisation of two highly resistant PR species isolated from these patients. The mutated proteases accumulated as much as 14 amino acid exchanges and develop resistance to saquinavir, ritonavir, indinavir and nelfinavir with vitality value up to 150. Kinetic analyses revealed that second-generation PI lopinavir and QF34 retained their subnanomolar potency against both multidrug resistant PR variants. These results suggest a route to the design of PIs capable of inhibiting a variety of resistant PR mutants. <p>

Title:Characterisation of Mutated Proteinases Derived from HIV-Positive Patients: Enzyme Activity, Vitality and Inhibition
Creators:
Kožíšek, Milan
Prejdová, Jana
Souček, Milan
Machala, Ladislav
Staňková, Marie
Linka, Marek
Brůčková, Marie
Konvalinka, Jan
Uncontrolled Keywords:HIV protease, Enzyme kinetics, Peptidomimetics, Viral resistance, Pseudopeptides, Enzyme inhibitors, AIDS, Antiviral drugs, Aspartic proteases
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:69
Number:3
Page Range:pp. 703-714
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc20040703UNSPECIFIED
ID Code:2238
Item Type:Article
Deposited On:06 Feb 2009 17:16
Last Modified:06 Feb 2009 16:16

Citation

Kožíšek, Milan; Prejdová, Jana; Souček, Milan; Machala, Ladislav; Staňková, Marie; Linka, Marek; Brůčková, Marie; Konvalinka, Jan (2004) Characterisation of Mutated Proteinases Derived from HIV-Positive Patients: Enzyme Activity, Vitality and Inhibition. Collection of Czechoslovak Chemical Communications, 69 (3). pp. 703-714. ISSN 0010-0765

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