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Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'-groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2003 In: Bioorganic and Medicinal Chemistry, Vol. 11, 1107-1115 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 11, 1107-1115 p.
Identifiers
URN: urn:nbn:se:uu:diva-92379OAI: oai:DiVA.org:uu-92379DiVA: diva2:165429
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved
In thesis
1. Structure-Assisted Design of Drugs Towards HIV-1 and Malaria Targets: Applied on Reverse Transcriptase and Protease from HIV-1 and Plasmepsin II from Plasmodium falciparum
Open this publication in new window or tab >>Structure-Assisted Design of Drugs Towards HIV-1 and Malaria Targets: Applied on Reverse Transcriptase and Protease from HIV-1 and Plasmepsin II from Plasmodium falciparum
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Globally of today, acquired immunodeficiency syndrome (AIDS) and malaria are two of the most threatening diseases known to mankind. The World Health Organization estimated that AIDS and malaria together claimed nearly 4 million lives in 2003 and many more were infected by the causative agent human immunodeficiency virus (HIV) and the Plasmodium falciparum (P. falicparum) parasite. Current treatment regims for HIV and P. falicparum infections are undermined by rapid emergence of drug-resistant strains and severe drug side-effects.

A resistance mechanism of the commonly selected K103N RT mutant towards three second generation non-nucleoside RT inhibitors (NNRTIs) is presented based on X-ray structures. Subtle changes in contacts between inhibitor and residue in position 103 aided the design of improved inhibitors. For the PR target, attempts have been made to structurally assist the development of diol-based protease inhibitors (PIs) with the aim of improving the anti-viral potency without reducing the inhibitory efficacy. It was shown that ortho- and meta-fluoro-substituted P1/P1’-benzyloxy side chains improved the anti-viral potency without affecting the accommodation to the S1/S1’ subsites.

The apparent increase in malaria resistance makes drug interventions of current targets increasingly complicated. A prominent new drug target is found in the parasite’s hemoglobin degradation pathway – the aspartic protease plasmepsin II (Plm II). The usefulness of Plm II as an anti-malarial target is presented supported by Plm II complexed with a novel inhibitor. Structurally it is shown that bulky P1- and P3-side-chains adopt a novel binding mode to the Plm II binding cleft with implications for further inhibitor development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 62 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 1040
Keyword
Molecular biology, X-ray crystallography, Drug design, HIV-1, Malaria, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-4667 (URN)91-554-6092-5 (ISBN)
Public defence
2004-12-10, B42, BMC, Husargatan 3, Uppsala, 13:00
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Supervisors
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved

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