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Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 14, 5413-5424 p.Article in journal (Refereed) Published
Abstract [en]

Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.

Place, publisher, year, edition, pages
2010. Vol. 18, no 14, 5413-5424 p.
Keyword [en]
HCV, Protease inhibitors, Peptidomimetics, Phenylglycine, Resistance, Alkenylic acylsulfonamides
National Category
Natural Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-129431DOI: 10.1016/j.bmc.2010.05.027ISI: 000279744700060PubMedID: 20541424OAI: oai:DiVA.org:uu-129431DiVA: diva2:343709
Available from: 2010-08-15 Created: 2010-08-15 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
Open this publication in new window or tab >>Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease.

The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 98 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 152
Keyword
hepatitis C virus, HCV, NS3 protease inhibitor, structure-activity relationship, phenylglycine, ring-closing metathesis
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-163361 (URN)978-91-554-8243-5 (ISBN)
Public defence
2012-02-03, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-01-13 Created: 2011-12-11 Last updated: 2012-01-16Bibliographically approved
2. Characterization of HCV Protease Inhibitors: Inhibition and Interaction Studies with Applications for Drug Discovery
Open this publication in new window or tab >>Characterization of HCV Protease Inhibitors: Inhibition and Interaction Studies with Applications for Drug Discovery
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, different approaches based on inhibition and interactions studies, have been used to characterize inhibitors of the non-structural protein 3 (NS3) from the hepatitis C virus (HCV). This involves identification of enzyme inhibitory effects and characterization of interaction mechanisms and kinetics, as well as effects on replication in a cell based system and serum protein binding. All this information contributes to HCV drug discovery.

By using an inhibition assay it was possible to evaluate the effects of NS3 protease inhibitors, tested or used in the clinic, on NS3 variants, representing different model systems often used for drug discovery. This study illustrates the importance of accounting for differences in catalytic properties in comparative analyses, for making relevant interpretations of inhibition data. An SPR biosensor-based assay expanded the first study, and provided kinetic and mechanistic information, by direct interaction analyses of the inhibitors. It revealed significant differences between the different genotypes and model systems, and provided data that can be used to better understand the efficacy of inhibitors.

Additionally, novel NS3 protease inhibitors were evaluated with respect to their potential to interfere with protease activity, their sensitivity to resistant mutants and effect on HCV replication. The most potent compounds were also characterized by their bioavailability, solubility and metabolic stability. This provides information for design of improved NS3 protease inhibitors, suggesting potential peptidomimetic structures for the backbone as well as for peptide substituents. These modification strategies allowed inhibitors to be truncated and less peptide-like, still with retained inhibitory effect.

A new strategy for analysis of serum protein binding, of importance for drug distribution was also developed. By defining and using the concept of binding efficiency, serum protein interactions of moderate affinity, as described by rapid kinetics, were characterized. This strategy is also applicable for analysis of low affinity interactions.

Taken together, all these studies provide knowledge and strategies for HCV drug discovery, and by using this information we might take a step closer to the final goal, which is to eradicate HCV.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1016
National Category
Natural Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-193256 (URN)978-91-554-8591-7 (ISBN)
Public defence
2013-03-15, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-02-22 Created: 2013-01-29 Last updated: 2013-02-28Bibliographically approved

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Gustafsson, Sofia S.Danielson, U. HelenaSandström, Anja

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