liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Medivir AB, Huddinge, Sweden.
Show others and affiliations
2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, 5136-5151 p.Article in journal (Refereed) Published
Abstract [en]

The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

Place, publisher, year, edition, pages
2006. Vol. 14, no 15, 5136-5151 p.
Keyword [en]
HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14308DOI: 10.1016/j.bmc.2006.04.008OAI: oai:DiVA.org:liu-14308DiVA: diva2:23195
Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2012-12-06Bibliographically approved
In thesis
1. Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.

Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.

Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 74 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1253
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-17850 (URN)978-91-7393-642-2 (ISBN)
Public defence
2009-05-15, Hörsal Planck, Campus Valla, Linköpings universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2014-01-09Bibliographically approved
2. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Incorporating a P2 Cyclopentane-Derived Scaffold
Open this publication in new window or tab >>Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Incorporating a P2 Cyclopentane-Derived Scaffold
2006 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi, 2006. 40 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1265
Keyword
HCV, NS3 protease, Proline mimic, Cyclopentane-derived scaffold, Linear inhibitors, Macrocyclic inhibitors
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-8395 (URN)91-85523-20-8 (ISBN)
Presentation
2006-09-26, Schrödinger, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 00:00 (English)
Opponent
Note
Report code: LIU-TEK-LIC-2006:46.Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2009-03-02
3. Design and synthesis of inhibitors that target the serine protease thrombin, the malarial aspartyl proteases plasmepsin I and II, and the hepatitis C virus NS3 serine protease
Open this publication in new window or tab >>Design and synthesis of inhibitors that target the serine protease thrombin, the malarial aspartyl proteases plasmepsin I and II, and the hepatitis C virus NS3 serine protease
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis addresses the design, synthesis, and structure-activity relationships of protease inhibitors that target the serine protease thrombin, the malarial aspartic proteases plasmepsin I and II, and the hepatitis C virus (HCV) NS3 serine protease. Furthermore, the backgrounds of each of the three types of diseases in question are discussed in detail, and consideration is given as to why it is assumed that inhibition of the mentioned proteases will help prevent or cure cardiovascular diseases, malaria, and hepatitis C.

The enzyme thrombin is a key factor in the blood coagulation cascade, and it is believed that inhibition of thrombin can have great implications in the treatment and prevention of a number of cardiovascular conditions, such as deep venous and arterial thrombosis, pulmonary embolism, and unstable angina. In the present research, we synthesized a series of potential thrombin inhibitors that incorporate novel morpholinonebased scaffolds derived from D(+)- and L(-)-malic acid mimicking proline in the thrombin-inhibiting tripeptide D-Phe-Pro-Arg. The most effective inhibitors in this series of compounds have IC50 values in the nanomolar to low micromolar range. We used the X-ray crystal structure to study the interactions between the best inhibitor and the active site of the enzyme.

Malaria is the most serious parasitic disease in the world, annually affecting approximately 500 million people and killing as many as two million. The malaria parasites degrade hemoglobin in the red blood cells as a source of the amino acids that are necessary for growth and maturation. A number of protease enzymes are involved in the breakdown of hemoglobin, and it is believed that the aspartic proteases plasmepsin I and II play important roles in this process. We developed a number of highly potent inhibitors of plasmepsins I and II that encompass modified statine motifs. In this endeavor, solid-phase combinatorial chemistry was used to synthesize libraries of compounds. The most promising compounds obtained from these libraries were further optimized by performing Suzuki couplings to yield inhibitors with Ki values in the picomolar range. Detailed information on the binding properties of these compounds was obtained by studying the X-ray crystal structure of an enzyme-inhibitor complex.

Hepatitis C is predominantly a chronic disease that afflicts 3% of the world's population, or about 170 million people. The virus, which in the long run leads to cirrhosis and liver cancer, is the leading indication for liver transplantation in the developed world. The HCV NS3 serine protease is essential for viral replication, because it is involved in processing the non-structural portion of a virally encoded polyprotein into functional enzymes. Thus, the NS3 protease has been recognized as one of the most important targets for the development of drugs used to fight HCV. We synthesized several potent and promising HCV NS3 inhibitors comprising a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. By systematically optimizing the substituents on this scaffold, we were able to identify very promising inhibitors in the nanomolar range.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 78 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 981
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-29722 (URN)15118 (Local ID)91-85457-57-4 (ISBN)15118 (Archive number)15118 (OAI)
Public defence
2005-11-25, Hörsal Planck, Fysikhuset, Campus Valla, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-12-06

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Johansson, Per-OlaBäck, MarcusKvarnström, IngemarRosenqvist, Åsa

Search in DiVA

By author/editor
Johansson, Per-OlaBäck, MarcusKvarnström, IngemarRosenqvist, Åsa
By organisation
ChemistryThe Institute of Technology
In the same journal
Bioorganic & Medicinal Chemistry
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 124 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf