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Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. (Organic Pharmaceutical Chemistry)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. (Organic Pharmaceutical Chemistry)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. (Organic Pharmaceutical Chemistry)
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2001 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 11, no 2, 203-206 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2001. Vol. 11, no 2, 203-206 p.
National Category
Pharmaceutical Sciences Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-51295DOI: 10.1016/S0960-894X(00)00625-9OAI: oai:DiVA.org:uu-51295DiVA: diva2:79204
Available from: 2006-03-04 Created: 2006-03-04 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors
Open this publication in new window or tab >>Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis C Virus (HCV) is the leading cause of chronic liver disease worldwide as well as the primary indication for liver transplantation. More than 3% of the world’s population is chronically infected with HCV and there is an urgent need for effective therapy. NS3 protease, a viral enzyme required for propagation of HCV in humans, is a promising target for drug development in this area. This thesis addresses the design, synthesis and biochemical evaluation of new HCV NS3 protease inhibitors.

The main objective of the thesis was the synthesis of peptide-based protease inhibitors of the bifunctional full-length NS3 enzyme (protease-helicase/NTPase). Three types of inhibitors were synthesized: i) classical serine protease inhibitors with electrophilic C-terminals, ii) product-based inhibitors with a C-terminal carboxylate group, and iii) product-based inhibitors with C-terminal carboxylic acid bioisosteres.

The developmental work included the establishment of an improved procedure for solid-phase peptide synthesis (SPPS) in the N-to-C direction, in contrast to the C-to-N direction of classical SPPS methods. This inverse method facilitated synthesis of the peptides modified at the C-terminal.

The potency of more than seventy newly synthesized inhibitors was assessed in an in vitro assay using the native form of the protease, i.e. the full-length NS3. The structure-activity relationship (SAR) data achieved was different from SAR data obtained from the more widely used truncated NS3 (protease domain) assay, indicating that the helicase domain of NS3 participates in the binding of the inhibitors.

The most potent inhibitors identified in this study contained a C-terminal phenyl acyl sulfonamide moiety, i.e. a carboxylic acid bioisostere. It is concluded that the acyl sulfonamide moiety is a promising P1-P1´ spanning entity, which may have potential for use in the development of more drug-like HCV protease inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 79 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 282
Keyword
Pharmaceutical chemistry, Farmaceutisk kemi
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-3311 (URN)91-554-5538-7 (ISBN)
Public defence
2003-03-21, Lecturehall B41, BMC, Uppsala, 10:15 (English)
Opponent
Available from: 2003-02-26 Created: 2003-02-26 Last updated: 2015-02-05Bibliographically approved

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Johansson, AnjaDanielson, U. Helena

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Organic Pharmaceutical ChemistryDepartment of Biochemistry
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