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Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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 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 17, 6512-6525 p.Article in journal (Refereed) Published
Abstract [en]

Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.

Place, publisher, year, edition, pages
2010. Vol. 18, no 17, 6512-6525 p.
Keyword [en]
Hepatitis C virus NS3 protease, Protease inhibitors, 2(1H)-pyrazinone, Phenylglycine
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-111366DOI: 10.1016/j.bmc.2010.06.101ISI: 000281203300032PubMedID: 20673728OAI: oai:DiVA.org:uu-111366DiVA: diva2:281506
Note

Uppdaterad från manuskript till Artikel 20101206

Available from: 2009-12-16 Created: 2009-12-11 Last updated: 2017-12-12Bibliographically approved
In thesis
1. On the Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: From Tripeptides to Achiral Compounds
Open this publication in new window or tab >>On the Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: From Tripeptides to Achiral Compounds
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infection by the hepatitis C virus (HCV) leads to inflammation of the liver, i.e. hepatitis. The acute infection often progresses to a chronic phase during which the liver function is gradually impaired. Approximately 20% of these chronic cases develop liver cirrhosis, with an ensuing increased risk of liver cancer. Global estimates of the total number of chronic cases range from 123–170 million. Yet, neither specific anti-HCV drugs nor vaccines are available. When drugs become available for daily clinical use, rapid development of drug-resistant strains is expected, making resistance an important issue.

One of the most studied targets for specific anti-HCV drugs is the NS3 protease. The main objectives of the work presented in this thesis were to design and synthesise peptidomimetic inhibitors of this enzyme, and to establish the structure–activity relationships (SARs) regarding the inhibition of the wild type as well as of the known resistant variants A156T and D168V.

Substituted prolines are common P2 residues in HCV NS3 protease inhibitors. To decrease the peptide character of the inhibitors, the non-coded phenylglycine was evaluated as a proline replacement in combination with known and novel P3 and P1 residues and P2 substituents. The results confirmed that phenylglycine is a promising P2 scaffold, with a possible π-stacking interaction with histidine 57 of the active site. However, to benefit from its full potential, additional optimisation is required.

A 2(1H)-pyrazinone-based scaffold was introduced as P3 residue. Utilising the scope of the method developed for the pyrazinone scaffold synthesis, the phenylglycine side-chain was transferred to the scaffold. In combination with an aromatic P1 building-block, this design yielded achiral, peptidomimetic inhibitors, three times more potent than the tripeptide lead.

The SARs for the inhibition of the resistant variants A156T and D168V were investigated for compounds based on either P2 proline or phenyl­glycine. It was concluded that the vulnerability of the inhibitors to alterations in the enzyme depends on the P2 and the P1 residue, not only on the P2 as previously suggested.

These results provide important information for the design of a new generation of inhibitors with improved properties.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 117
Keyword
hepatitis C virus, NS3 protease inhibitor, structure-activity relationship, resistance, 2(1H)-pyrazinone, phenylglycine
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-110738 (URN)978-91-554-7692-2 (ISBN)
Public defence
2010-02-12, B21, Biomedicinskt center (BMC), Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2010-01-20 Created: 2009-11-24 Last updated: 2010-01-21
2. Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases: Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
Open this publication in new window or tab >>Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases: Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.

The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 160
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-172341 (URN)978-91-554-8345-6 (ISBN)
Public defence
2012-05-25, BMC, B42, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-03 Created: 2012-04-04 Last updated: 2012-08-01Bibliographically approved

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Gising, JohanEhrenberg, AngelicaBorg, AnneliKarlén, AndersLarhed, MatsDanielson, U. HelenaSandström, Anja

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