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Viruses 2017, 9(6), 151; doi:10.3390/v9060151

Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase

Department of Chemistry—BMC, Uppsala University, SE-751 23 Uppsala, Sweden
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Academic Editor: Curt Hagedorn
Received: 15 May 2017 / Revised: 5 June 2017 / Accepted: 8 June 2017 / Published: 16 June 2017
(This article belongs to the Section Antivirals & Vaccines)
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Abstract

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. View Full-Text
Keywords: hepatitis C virus (HCV); non-structural protein (NS) polymerase; genotypes; allosteric inhibitor; surface plasmon resonance (SPR) hepatitis C virus (HCV); non-structural protein (NS) polymerase; genotypes; allosteric inhibitor; surface plasmon resonance (SPR)
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MDPI and ACS Style

Abdurakhmanov, E.; Øie Solbak, S.; Danielson, U.H. Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase. Viruses 2017, 9, 151.

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