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Discovery of the subsite specificity of Candida albicans Sap1 and Sap2 and the design of potent peptidomimetic inhibitors
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(English)Manuscript (Other (popular science, discussion, etc.))
URN: urn:nbn:se:uu:diva-93113OAI: oai:DiVA.org:uu-93113DiVA: diva2:166492
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2009-11-27Bibliographically approved
In thesis
1. Interaction Studies of Secreted Aspartic Proteases (Saps) from Candida albicans: Application for Drug Discovery
Open this publication in new window or tab >>Interaction Studies of Secreted Aspartic Proteases (Saps) from Candida albicans: Application for Drug Discovery
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on enzymatic studies of the secreted aspartic proteases (Saps) from Candida albicans as a tool for discovery of anti-candida drugs. C. albicans causes infections in a number of different locations, which differ widely in the protein substrates available and pH. Since C. albicans needs Saps during virulent growth, these enzymes are good targets for drug development.

In order to investigate the catalytic characteristics of Saps and their inhibitor affinities, substrate-based kinetic assays were developed. Due to the low sensitivity of these assays, especially at the sub-optimal pH required to mimic the different locations of infections, these assays were not satisfactory. Therefore, a biosensor assay was developed whereby, it was possible to study interaction between Saps and inhibitors without the need to optimise catalytic efficacy. Furthermore, the biosensor assay allowed determination of affinity, as well as the individual association and dissociation rates for inhibitor interactions.

Knowledge about substrate specificity, Sap subsite adaptivity, and the pH dependencies of catalytic efficacy has been accumulated. Also, screening of transition-state analogue inhibitors designed for HIV-1 protease has revealed inhibitors with affinity for Saps. Furthermore, the kinetics and pH dependencies of their interaction with Saps have been investigated. One of these inhibitors, BEA-440, displayed a complex interaction with Saps, indicating a conformational change upon binding and a very slow dissociation rate. A time dependent interaction was further supported by inhibition measurements. The structural information obtained affords possibilities for design of new more potent inhibitors that might ultimately become drugs against candidiasis. The strategy to combine substrate specificity studies with inhibitor screening has led to complementary results that generate a framework for further development of potent inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 58
Biochemistry, SPR Biosensor, Secreted aspartic proteases, Candida albicans, interaction kinetics, drug discovery, protease inhibitor, Biokemi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-5815 (URN)91-554-6263-4 (ISBN)
Public defence
2005-06-03, Room C8:305, BMC, Husargatan 3, Uppsala, 13:15
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2012-04-13Bibliographically approved

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Danielson, U. Helena
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