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Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0003-2728-0340
2017 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 6, article id 151Article in journal (Refereed) Published
Abstract [en]

Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

Place, publisher, year, edition, pages
2017. Vol. 9, no 6, article id 151
Keywords [en]
hepatitis C virus (HCV), non-structural protein (NS) polymerase, genotypes, allosteric inhibitor, surface plasmon resonance (SPR)
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-331940DOI: 10.3390/v9060151ISI: 000405832000026OAI: oai:DiVA.org:uu-331940DiVA, id: diva2:1152352
Funder
Swedish Research Council, D0571301Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2017-11-29Bibliographically approved

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