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Proteochemometric Modeling of the Susceptibility of Mutated Variants of the HIV-1 Virus to Reverse Transcriptase Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Wikberg group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Wikberg group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Wikberg group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Wikberg group)ORCID iD: 0000-0002-8083-2864
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2010 (English)In: PLoS ONE, ISSN eISSN-1932-6203, Vol. 5, no 12, e14353- p.Article in journal (Refereed) Published
Abstract [en]

Background

Reverse transcriptase is a major drug target in highly active antiretroviral therapy (HAART) against HIV, which typically comprises two nucleoside/nucleotide analog reverse transcriptase (RT) inhibitors (NRTIs) in combination with a non-nucleoside RT inhibitor or a protease inhibitor. Unfortunately, HIV is capable of escaping the therapy by mutating into drug-resistant variants. Computational models that correlate HIV drug susceptibilities to the virus genotype and to drug molecular properties might facilitate selection of improved combination treatment regimens.

Methodology/Principal Findings

We applied our earlier developed proteochemometric modeling technology to analyze HIV mutant susceptibility to the eight clinically approved NRTIs. The data set used covered 728 virus variants genotyped for 240 sequence residues of the DNA polymerase domain of the RT; 165 of these residues contained mutations; totally the data-set covered susceptibility data for 4,495 inhibitor-RT combinations. Inhibitors and RT sequences were represented numerically by 3D-structural and physicochemical property descriptors, respectively. The two sets of descriptors and their derived cross-terms were correlated to the susceptibility data by partial least-squares projections to latent structures. The model identified more than ten frequently occurring mutations, each conferring more than two-fold loss of susceptibility for one or several NRTIs. The most deleterious mutations were K65R, Q151M, M184V/I, and T215Y/F, each of them decreasing susceptibility to most of the NRTIs. The predictive ability of the model was estimated by cross-validation and by external predictions for new HIV variants; both procedures showed very high correlation between the predicted and actual susceptibility values (Q2 = 0.89 and Q2ext = 0.86). The model is available at www.hivdrc.org as a free web service for the prediction of the susceptibility to any of the clinically used NRTIs for any HIV-1 mutant variant.

Conclusions/Significance

Our results give directions how to develop approaches for selection of genome-based optimum combination therapy for patients harboring mutated HIV variants.

Place, publisher, year, edition, pages
2010. Vol. 5, no 12, e14353- p.
National Category
Pharmacology and Toxicology
Research subject
Bioinformatics; Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-141096DOI: 10.1371/journal.pone.0014353ISI: 000285340000015PubMedID: 21179544OAI: oai:DiVA.org:uu-141096DiVA: diva2:384972
Available from: 2011-01-10 Created: 2011-01-10 Last updated: 2015-05-04Bibliographically approved
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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Lapins, MarisEklund, MartinSpjuth, OlaWikberg, Jarl

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