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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
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
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: urn:nbn:se:liu:diva-29722Local ID: 15118ISBN: 91-85457-57-4 (print)OAI: oai:DiVA.org:liu-29722DiVA: diva2:250539
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
List of papers
1. Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
Open this publication in new window or tab >>Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
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2002 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 6, 1829-1839 p.Article in journal (Refereed) Published
Abstract [en]

A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-47039 (URN)10.1016/S0968-0896(02)00023-8 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2012-12-06
2. Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II: use of solid-phase synthesis to explore novel statine motifs
Open this publication in new window or tab >>Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II: use of solid-phase synthesis to explore novel statine motifs
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2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 13, 3353-3366 p.Article in journal (Refereed) Published
Abstract [en]

Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-86056 (URN)10.1021/jm031106i (DOI)
Available from: 2012-12-06 Created: 2012-12-06 Last updated: 2017-12-07
3. Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II
Open this publication in new window or tab >>Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II
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2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 13, 4400-4409 p.Article in journal (Refereed) Published
Abstract [en]

New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-50477 (URN)10.1021/jm040884n (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2012-12-06
4. Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
Open this publication in new window or tab >>Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
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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.

Keyword
HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-14308 (URN)10.1016/j.bmc.2006.04.008 (DOI)
Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2012-12-06Bibliographically approved

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Johansson, Per-Ola

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