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Design and Evaluation of Dengue NS3 Protease Peptide Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Laboratory of Molecular and Cellular Microbiology, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhorpathom, Thailand.
Laboratory of Molecular and Cellular Microbiology, Institute of Molecular Biosciences, Singapore.
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-173501OAI: oai:DiVA.org:uu-173501DiVA: diva2:523592
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2013-04-11
In thesis
1. Studies of Retroviral Reverse Transcriptase and Flaviviral Protease Enzymes as Antiviral Drug Targets: Applications in Antiviral Drug Discovery & Therapy
Open this publication in new window or tab >>Studies of Retroviral Reverse Transcriptase and Flaviviral Protease Enzymes as Antiviral Drug Targets: Applications in Antiviral Drug Discovery & Therapy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Viruses are a major threat to humans due to their unique adaptability, evolvability and  capability to control their hosts as parasites and genetic elements. HIV/AIDS is the third largest cause of death by infectious diseases in the world, and drug resistance due to the viral mutations is still the leading cause of treatment failure. The flaviviruses, such as Dengue virus (DEN) and Japanese encephalitis virus (JEV), represent other major cause of morbidity and mortality, and the areas where these viruses are endemic are spreading rapidly. No curative therapy for any flavivirus could be made available as yet.

The first part of this thesis focuses on the HIV-1 drug resistance caused by mutations in a major HIV drug target, the HIV-1 reverse transcriptase (RT) as a response to the largest class of clinically used anti-retrovirals, the NRTIs. A robust proteochemometric model was created to analyse the complex mutation patterns in RT drug resistance. The model identified more than ten frequently-occurring mutations, each conferring at least two-fold decrease in susceptibility for one or several NRTIs. Using our prediction server (hivdrc.org), the model can be applied to propose optimum combination therapy for patients harbouring mutated HIV variants.

The second part of the thesis encompasses studies on a promising drug target, the NS2B(H)-NS3pro, in two flaviviruses, namely the dengue virus (DEN) and Japanese encephalitis virus (JEV). Functional determinants of DEN NS2B(H)-NS3pro were identified by site-directed mutagenesis. Further, peptide inhibitors were designed using proteochemometrics (PCM) and statistical molecular design (SMD), synthesized and assayed on DEN proteases, which resulted in some novel peptides with low micromolar or sub-micromolar inhibitor activity. The very poorly characterised JEV NS2B(H)-NS3pro  was cloned, purified and the kinetic parameters of this attractive drug target were determined for a series of model substrates and inhibitor. The results identified the role in target-ligand interaction of different residues on specific positions in the target (NS2B(H)-NS3pro) and ligands (substrates/inhibitors).

Overall, the findings in this thesis contribute to rational antiviral drug discovery and therapy.

Place, publisher, year, edition, pages
Acta Universitatis Upsaliensis: Uppsala universitet, 2012. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 163
Keyword
Virus, enzymes, HIV/AIDS, retroviral reverse transcriptase, flaviviral protease, NRTIs, proteochemometrics, drug resistance, DEN, JEV, NS2B(H)-NS3pro, antiviral, drug targets, drug discovery, drug therapy.
National Category
Pharmaceutical Sciences
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-173504 (URN)978-91-554-8388-3 (ISBN)
Public defence
2012-06-14, C4:305, BMC, Husargatan 3, Uppsala, 09:00 (English)
Supervisors
Available from: 2012-05-23 Created: 2012-04-25 Last updated: 2012-08-01Bibliographically approved

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