uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Novel peptidomimetic HCV NS3 protease inhibitors spanning the P2-P1´ region
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-193250OAI: oai:DiVA.org:uu-193250DiVA: diva2:601585
Available from: 2013-01-29 Created: 2013-01-29 Last updated: 2014-03-09
In thesis
1. Characterization of HCV Protease Inhibitors: Inhibition and Interaction Studies with Applications for Drug Discovery
Open this publication in new window or tab >>Characterization of HCV Protease Inhibitors: Inhibition and Interaction Studies with Applications for Drug Discovery
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, different approaches based on inhibition and interactions studies, have been used to characterize inhibitors of the non-structural protein 3 (NS3) from the hepatitis C virus (HCV). This involves identification of enzyme inhibitory effects and characterization of interaction mechanisms and kinetics, as well as effects on replication in a cell based system and serum protein binding. All this information contributes to HCV drug discovery.

By using an inhibition assay it was possible to evaluate the effects of NS3 protease inhibitors, tested or used in the clinic, on NS3 variants, representing different model systems often used for drug discovery. This study illustrates the importance of accounting for differences in catalytic properties in comparative analyses, for making relevant interpretations of inhibition data. An SPR biosensor-based assay expanded the first study, and provided kinetic and mechanistic information, by direct interaction analyses of the inhibitors. It revealed significant differences between the different genotypes and model systems, and provided data that can be used to better understand the efficacy of inhibitors.

Additionally, novel NS3 protease inhibitors were evaluated with respect to their potential to interfere with protease activity, their sensitivity to resistant mutants and effect on HCV replication. The most potent compounds were also characterized by their bioavailability, solubility and metabolic stability. This provides information for design of improved NS3 protease inhibitors, suggesting potential peptidomimetic structures for the backbone as well as for peptide substituents. These modification strategies allowed inhibitors to be truncated and less peptide-like, still with retained inhibitory effect.

A new strategy for analysis of serum protein binding, of importance for drug distribution was also developed. By defining and using the concept of binding efficiency, serum protein interactions of moderate affinity, as described by rapid kinetics, were characterized. This strategy is also applicable for analysis of low affinity interactions.

Taken together, all these studies provide knowledge and strategies for HCV drug discovery, and by using this information we might take a step closer to the final goal, which is to eradicate HCV.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1016
National Category
Natural Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-193256 (URN)978-91-554-8591-7 (ISBN)
Public defence
2013-03-15, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-02-22 Created: 2013-01-29 Last updated: 2013-02-28Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Bergman, SaraSandström, Anja

Search in DiVA

By author/editor
Bergman, SaraSandström, Anja
By organisation
Organic Pharmaceutical ChemistryDepartment of Chemistry - BMCDepartment of Pharmacy
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 31343 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf