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Mechanistic studies of electrophilic protease inhibitors of full length hepatic C virus (HCV) NS3
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. (ORGFARM)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. (ORGFARM)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
2007 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 22, no 2, 191-199 p.Article in journal (Refereed) Published
Abstract [en]

The inhibition mechanism of electrophilic peptide-based protease inhibitors of full-length hepatitis C virus (HCV) NS3 has been investigated by determining the Ki-values for a series of compounds differing in the electrophilicity and acidity of the C-terminal residue at pH-values above and below the pKa of the catalytic histidine (6.85) and at two different ionic strengths. Electrophilic compounds with a pentafluoroethyl ketone group showed stronger inhibition at pH 8 than pH 6, as expected for a mechanism requiring an unprotonated catalytic histidine. However, the difference was only significant at high ionic strength. In contrast, electrophilic compounds with an acidic C-terminal group or a cyclic P1 residue showed a lower inhibitory effect at pH 8 than at pH 6, inconsistent with a mechanism-based inhibition. Moreover, all electrophilic compounds had an unexpectedly strong inhibition at pH 6, when mechanism-based inhibition is unlikely. The results suggest that for some of the electrophilic compounds the reactive group may not be properly positioned in the active site and that binding of these inhibitors is a result of non-covalent interactions. The nature of these interactions is discussed.

Place, publisher, year, edition, pages
2007. Vol. 22, no 2, 191-199 p.
Keyword [en]
Hepatitis C virus, NS3 protease, serine protease, inhibition, electrophilic inhibitors
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-17090DOI: 10.1080/14756360601072916ISI: 000246325900009PubMedID: 17518346OAI: oai:DiVA.org:uu-17090DiVA: diva2:44861
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2017-12-08Bibliographically approved

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Sandström, AnjaÅkerblom, EvaDanielson, U. Helena

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