Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap 1, Sap 2, and Sap 3 from Candida albicans

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Serval ID
serval:BIB_D8B932D44BAB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap 1, Sap 2, and Sap 3 from Candida albicans
Journal
Journal of Biomolecular Screening
Author(s)
Backman  D., Monod  M., Danielson  U. H.
ISSN
1087-0571 (Print)
Publication state
Published
Issued date
03/2006
Volume
11
Number
2
Pages
165-75
Notes
Journal Article
Research Support, Non-U.S. Gov't
Validation Studies --- Old month value: Mar
Abstract
A surface plasmon resonance (SPR) biosensor-based strategy for identification and characterization of compounds has been devised as a tool for the discovery of specific drugs for treatment of Candida albicans infections. Three secreted aspartic proteases (Saps 1-3) from C. albicans were used as parallel targets. The stepwise procedure involved screening of 104 HIV-1 pro-tease inhibitors at a single concentration for binding to the targets. Twenty-four compounds that appeared to interact with the targets were identified in the screen. False positives and compounds with low affinities or very fast dissociation rates could be removed after a series of additional measurements of these compounds at 3 different concentrations. Kinetic characterization was performed with 13 compounds, giving information about the interaction mechanism and interaction kinetic parameters (k(on), k(off), and K(D)). The pH dependence of the interaction and the inhibitory effect of a final small set of compounds were also evaluated. The strategy resulted in the identification of ritonavir as the compound generally exhibiting the highest affinity for the Candida enzymes. It had similar interaction kinetic characteristics for Sap 1 and Sap 2 but a lower affinity for Sap 3 due to a slower association rate. Several additional compounds with high affinity and/or slow dissociation rates for the targets were identified, revealing 2 other structural scaffolds for Sap inhibitors. In addition, important differences in the specificity for these types of compounds by the Saps were identified. The stepwise biosensor-based strategy was consequently efficient for identification and characterization of new lead compounds for 3 important drug targets.
Keywords
Aspartic Endopeptidases/*chemistry/metabolism Biosensing Techniques/*methods Candida albicans/*enzymology Drug Interactions Fungal Proteins/*chemistry/metabolism HIV Protease Inhibitors/*chemistry Hydrogen-Ion Concentration Isoenzymes/chemistry Models, Molecular Pepstatins/chemistry Ritonavir/*pharmacology
Pubmed
Web of science
Create date
25/01/2008 16:46
Last modification date
20/08/2019 15:58
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