uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.ORCID-id: 0000-0003-2728-0340
2017 (engelsk)Inngår i: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, nr 6, artikkel-id 151Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2017. Vol. 9, nr 6, artikkel-id 151
Emneord [en]
hepatitis C virus (HCV), non-structural protein (NS) polymerase, genotypes, allosteric inhibitor, surface plasmon resonance (SPR)
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-331940DOI: 10.3390/v9060151ISI: 000405832000026OAI: oai:DiVA.org:uu-331940DiVA, id: diva2:1152352
Forskningsfinansiär
Swedish Research Council, D0571301Tilgjengelig fra: 2017-10-24 Laget: 2017-10-24 Sist oppdatert: 2017-11-29bibliografisk kontrollert

Open Access i DiVA

fulltext(2660 kB)149 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 2660 kBChecksum SHA-512
15c2000d483dac1f94644f6d0420efc21dec9c2ed85a4704102f368d81bf2701ec351c2793639b0a1e92025a4676ce0298e3ee563381cd335db7bd4b3973a4ab
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekst

Personposter BETA

Abdurakhmanov, EldarDanielson, U. Helena

Søk i DiVA

Av forfatter/redaktør
Abdurakhmanov, EldarDanielson, U. Helena
Av organisasjonen
I samme tidsskrift
Viruses

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 149 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
urn-nbn

Altmetric

doi
urn-nbn
Totalt: 1185 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf