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Pyrazinone based hepatitis C virus NS3 protease inhibitors targeting genotype 1a, 3a and the drug-resistant enzyme variant R155K
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-265295OAI: oai:DiVA.org:uu-265295DiVA: diva2:865034
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
In thesis
1. Discovery and evaluation of direct acting antivirals against hepatitis C virus
Open this publication in new window or tab >>Discovery and evaluation of direct acting antivirals against hepatitis C virus
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Until recently, the standard therapy for hepatitis C treatment has been interferon and ribavirin. Such treatment has only 50% efficacy and is not well tolerated. The emergence of new drugs has increased the treatment efficacy to 90%. Despite such an achievement, the success is limited since the virus mutates rapidly, causing the emergence of drug resistant forms. In addition, most new drugs were developed to treat genotype 1 infections. Thus, development of new potent antivirals is needed and drug discovery against hepatitis C is continued.

In this thesis, a FRET-based protease assay was used to evaluate new pyrazinone based NS3 protease inhibitors that are structurally different to the newly approved and currently developing drugs. Several compounds in this series showed good potencies in the nanomolar range against NS3 proteases from genotype 1, 3, and the drug resistance variant R155K. We assume that these compounds can be further developed into drug candidates that possess activity against above mentioned enzyme variants.

By using SPR technology, we analyzed interaction mechanisms and characteristics of allosteric inhibitors targeting NS5B polymerases from genotypes 1 and 3. The compounds exhibited different binding mechanisms and displayed a low affinity against NS5B from genotype 3.

In order to evaluate the activity and inhibitors of the NS5B polymerase, we established an SPR based assay, which enables the monitoring of polymerization and its inhibition in real time. This assay can readily be implemented for the discovery of inhibitors targeting HCV.

An SPR based fragment screening approach has also been established. A screen of a fragment library has been performed in order to identify novel scaffolds that can be used as a starting point for development of new allosteric inhibitors against NS5B polymerase. Selected fragments will be further elaborated to generate a new potent allosteric drug candidate.

Alternative approaches have successfully been developed and implemented to the discovery of potential lead compounds targeting two important HCV drug targets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1312
Direct acting antivirals, Hepatitis C, NS3-4A protease, NS5B polymerase, structure-based drug discovery, fragment-based drug discovery, surface plasmon resonance
National Category
Biochemistry and Molecular Biology
Research subject
urn:nbn:se:uu:diva-265299 (URN)978-91-554-9398-1 (ISBN)
Public defence
2015-12-18, B21, BMC, Husargatan 3, Uppsala, 09:00 (English)
Available from: 2015-11-27 Created: 2015-10-26 Last updated: 2016-01-13

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