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Symmetric fluoro-substituted diol-based HIV protease inhibitors: Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2004 (English)In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 271, no 22, 4594-4602 p.Article in journal (Refereed) Published
Abstract [en]

HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 A resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluoro-substitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

Place, publisher, year, edition, pages
2004. Vol. 271, no 22, 4594-4602 p.
Keyword [en]
Amino Acids/chemistry/metabolism, Benzene Derivatives/*chemistry/metabolism/*pharmacology, Binding Sites, Crystallography; X-Ray, Electrostatics, Escherichia coli/genetics/metabolism, HIV Protease/chemistry/genetics/metabolism, HIV Protease Inhibitors/*chemistry/metabolism/*pharmacology, HIV-1/*enzymology, Humans, Hydrocarbons; Fluorinated/*chemistry/metabolism/*pharmacology, Models; Molecular, Molecular Conformation, Molecular Structure, Protein Binding, Recombinant Proteins/antagonists & inhibitors/chemistry/genetics/metabolism, Research Support; Non-U.S. Gov't, Structure-Activity Relationship
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-92378DOI: 10.1111/j.1432-1033.2004.04431.xPubMedID: 15560801OAI: oai:DiVA.org:uu-92378DiVA: diva2:165428
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2013-07-10Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 1040
Molecular biology, X-ray crystallography, Drug design, HIV-1, Malaria, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-4667 (URN)91-554-6092-5 (ISBN)
Public defence
2004-12-10, B42, BMC, Husargatan 3, Uppsala, 13:00
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved

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