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Identification of complexities in HIV-1 protease - ligand interactions using biosensor technology
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
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(English)Manuscript (Other (popular science, discussion, etc.))
URN: urn:nbn:se:uu:diva-92357OAI: oai:DiVA.org:uu-92357DiVA: diva2:165400
Available from: 2004-11-12 Created: 2004-11-12 Last updated: 2009-11-27Bibliographically approved
In thesis
1. Exploring Inhibitors of HIV-1 Protease: Interaction Studies with Applications for Drug Discovery
Open this publication in new window or tab >>Exploring Inhibitors of HIV-1 Protease: Interaction Studies with Applications for Drug Discovery
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A variety of HIV-1 protease inhibitors and their interactions with the enzyme have been characterized in order to identify novel and improved drugs against AIDS. The investigated inhibitors were represented by clinical and non-clinical inhibitors, active site and allosteric inhibitors, transition-state analogues and metal-ions. In addition, different enzyme variants were used to investigate the contribution of different amino acid residues to the interaction with different ligands. The problem of resistance has been addressed by exploring novel types of inhibitors, and resistant mutants of HIV-1 protease. A study resolving the inhibition of HIV-1 protease by Cu2+ showed that the enzyme can be allosterically inhibited and that copper inhibition is a result of an interaction with His-69 and a subsequent conformational change. Several types of transition-state analogues were analyzed with respect to their inhibition of wild-type and resistant mutants of HIV-1 protease. Unfortunately cyclic compounds were not found to be better than linear compounds. Moreover, it was not possible to identify structure-activity relationships that clearly correlated with efficacy towards mutants and a biosensor based method for more detailed kinetic studies was therefore adopted. By cross-linking the immobilized enzyme on the biosensor matrix, a stable surface was obtained and kinetic rate constants could be determined for the interaction between the enzyme and inhibitors. Additional improvements in the methodology involved identification of a more representative interaction model, allowing more detailed studies of interactions with resistant mutants and varying conditions. Finally, absorption to lipid membranes and interaction with human serum albumin and α1-glycoprotein by clinical drugs were studied in a simplified ADME model system for improvement of the earlier stages of drug development. These studies have revealed important characteristics of these drugs that can potentially be modeled into new compounds that have improved efficacy of both wild-type and resistant mutants of HIV-1 protease.

Place, publisher, year, edition, pages
Uppsala: Institutionen för naturvetenskaplig biokemi, 2004. 47 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 1038
Biochemistry, kinetics, biosensors, ADME, drug discovery, SPR, resistance, inhibition, copper, Biokemi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-4655 (URN)91-554-6087-9 (ISBN)
Public defence
2004-12-03, B41, BMC, Husargatan 3, Uppsala, 13:30 (English)
Available from: 2004-11-12 Created: 2004-11-12 Last updated: 2012-04-13Bibliographically approved

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Danielson, U. Helena
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