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Design and Synthesis of Malarial Aspartic Protease Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria is one of the major public health problems in the world. Approximately 500 million people are afflicted and almost 3 million people die from the disease each year. Of the four causative species Plasmodium falciparum is the most lethal. Due to the rapid spread of parasite resistance there is an urgent need for new antimalarial drugs with novel mechanisms of action. Several promising targets for drug intervention have been revealed.

This thesis addresses the parasitic aspartic proteases termed plasmepsins (Plm), which are considered crucial to the hemoglobin catabolism essential for parasite survival. The overall aim was to identify inhibitors of the P. falciparum Plm I, II, and IV. More specific objectives were to attain activity against P. falciparum in infected erythrocytes and selectivity versus the most homologous human aspartic protease cathepsin D (Cat D). To guide the design process the linear interaction energy (LIE) method was employed in combination with molecular dynamics.

Initial investigations of the stereochemical requirements for inhibition resulted in identification of an L-mannitol derived scaffold encompassing a 1,2-dihydroxyethylene transition state isostere with affinity for Plm II. Further modifications of this scaffold provided inhibitors of all three target plasmepsins (Plm I, II, and IV). Apart from the stereochemical analysis three major kinds of manipulation were explored: a) P1/P1′ and P2/P2′ side chain alterations, b) replacement of amide bonds by diacylhydrazine, 1,3,4-oxadiazole, and 1,2,4-triazole, and c) macrocyclization. Several inhibitors of Plm I and II with Ki values below 10 nM were discovered and one Plm IV selective inhibitor comprising two oxadiazole rings was found which represents the most potent non-peptide Plm IV inhibitor (Ki = 35 nM) reported to date. Some of the identified plasmepsin inhibitors demonstrated significant activity against P. falciparum in infected erythrocytes and all inhibitors showed a considerable selectivity for the plasmepsins over the human Cat D.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 93
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 5
Keywords [en]
Pharmaceutical chemistry, malaria, plasmepsin, aspartic protease, protease inhibitor, macrocycle
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-4833ISBN: 91-554-6177-8 (print)OAI: oai:DiVA.org:uu-4833DiVA, id: diva2:165921
Public defence
2005-04-15, B41, Uppsala Biomedical Centre (BMC), Husarg. 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2005-03-23 Created: 2005-03-23 Last updated: 2018-01-13Bibliographically approved
List of papers
1. C2-Symmetric Inhibitors of Plasmodium falciparum Plasmepsin II: Synthesis and Theoretical Predictions
Open this publication in new window or tab >>C2-Symmetric Inhibitors of Plasmodium falciparum Plasmepsin II: Synthesis and Theoretical Predictions
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2003 In: Bioorganic and Medicinal Chemistry, Vol. 22, no 17, p. 3723-3733Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92733 (URN)
Available from: 2005-03-23 Created: 2005-03-23Bibliographically approved
2. Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity
Open this publication in new window or tab >>Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity
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2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 1, p. 110-22Article in journal (Refereed) Published
Keywords
Amides/*chemical synthesis/chemistry/pharmacology, Animals, Aspartic Endopeptidases/*antagonists & inhibitors/chemistry, Cathepsin D/*antagonists & inhibitors, Cells; Cultured, Computer Simulation, Erythrocytes/parasitology, Ethylenes/*chemistry, Humans, Models; Molecular, Molecular Conformation, Plasmodium falciparum/drug effects/*enzymology, Protein Binding, Research Support; Non-U.S. Gov't, Stereoisomerism, Structure-Activity Relationship, Thermodynamics
National Category
Pharmaceutical Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-72743 (URN)10.1021/jm030933g (DOI)14695825 (PubMedID)
Available from: 2005-05-27 Created: 2005-05-27 Last updated: 2018-01-14Bibliographically approved
3. Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations
Open this publication in new window or tab >>Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92735 (URN)
Available from: 2005-03-23 Created: 2005-03-23Bibliographically approved
4. Macrocyclic Inhibitors of the Malarial Aspartic Proteases Plasmepsin I, II, and IV
Open this publication in new window or tab >>Macrocyclic Inhibitors of the Malarial Aspartic Proteases Plasmepsin I, II, and IV
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92736 (URN)
Available from: 2005-03-23 Created: 2005-03-23 Last updated: 2010-01-13Bibliographically approved

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