Abstract
Viruses have been found to exhibit protein kinase activity associated with their purified viral particles. HIV-1 virus particles possess a novel 72 kD protein, Topoisomerase II beta kinase (Topo IIβKHIV) activity. The enzyme, isolated and purified from PEGprecipitated HIV-1 particles, is insensitive against a diverse set of known kinase inhibitors. The pyridine derivatives were found to be active against both Topo IIβKHIV activity and HIV-1 replication. For both kinase antagonism and anti-HIV-1 activity the Comparative Molecular Field Analysis (CoMFA) models were proposed. The CoMFA model was also evaluated independently with a set of test molecules for their anti-viral activity. The kinase inhibition and anti-viral activities for these inhibitors, tested in an in vitro kinase agree with the CoMFA model (cross-validated r2 (q2) value of 0.642 with six principal components), lower acceptable results are obtained with anti- HIV-1 activity (cross-validated r2 (q2) value of 0.358 with four principal components) and also correlate with relative solvation free energy calculations. The predictive power of the models was evaluated with 2 test molecules each and tends to lie within 1 log unit. An in cell validation of the model with a representative inhibitor, 2-methoxypyridine shows its ability to inhibit Topo IIβ phosphorylation during acute HIV-1 infection. Close correlation of molecular fields of inhibitory domains of kinase and HIV-1 inhibitors suggests specificity of action of pyridine derivatives in affecting HIV-1 replication through inhibition of Kinase activity. These investigations suggest that Topo IIβKHIV is a potential target for an effective control of HIV-1 replication that would help in developing new anti-retroviral molecules.
Keywords: HIV-1, HIV-1-Topoisomerase IIβ, Topoisomerase IIβ, HIV-1 associated Topoisomerase IIβ Kinase, Synthesis of anti-HIV and anti-Kinase Inhibitors, QSAR.
Current Pharmaceutical Design
Title:HIV-1 Associated Topoisomerase IIβ Kinase: A Potential Pharmacological Target for Viral Replication
Volume: 19 Issue: 26
Author(s): Kannapiran Ponraj, Maddela Prabhakar, R.S. Rathore, Akhila Bommakanti and Anand K. Kondapi
Affiliation:
Keywords: HIV-1, HIV-1-Topoisomerase IIβ, Topoisomerase IIβ, HIV-1 associated Topoisomerase IIβ Kinase, Synthesis of anti-HIV and anti-Kinase Inhibitors, QSAR.
Abstract: Viruses have been found to exhibit protein kinase activity associated with their purified viral particles. HIV-1 virus particles possess a novel 72 kD protein, Topoisomerase II beta kinase (Topo IIβKHIV) activity. The enzyme, isolated and purified from PEGprecipitated HIV-1 particles, is insensitive against a diverse set of known kinase inhibitors. The pyridine derivatives were found to be active against both Topo IIβKHIV activity and HIV-1 replication. For both kinase antagonism and anti-HIV-1 activity the Comparative Molecular Field Analysis (CoMFA) models were proposed. The CoMFA model was also evaluated independently with a set of test molecules for their anti-viral activity. The kinase inhibition and anti-viral activities for these inhibitors, tested in an in vitro kinase agree with the CoMFA model (cross-validated r2 (q2) value of 0.642 with six principal components), lower acceptable results are obtained with anti- HIV-1 activity (cross-validated r2 (q2) value of 0.358 with four principal components) and also correlate with relative solvation free energy calculations. The predictive power of the models was evaluated with 2 test molecules each and tends to lie within 1 log unit. An in cell validation of the model with a representative inhibitor, 2-methoxypyridine shows its ability to inhibit Topo IIβ phosphorylation during acute HIV-1 infection. Close correlation of molecular fields of inhibitory domains of kinase and HIV-1 inhibitors suggests specificity of action of pyridine derivatives in affecting HIV-1 replication through inhibition of Kinase activity. These investigations suggest that Topo IIβKHIV is a potential target for an effective control of HIV-1 replication that would help in developing new anti-retroviral molecules.
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Ponraj Kannapiran, Prabhakar Maddela, Rathore R.S., Bommakanti Akhila and Kondapi K. Anand, HIV-1 Associated Topoisomerase IIβ Kinase: A Potential Pharmacological Target for Viral Replication, Current Pharmaceutical Design 2013; 19 (26) . https://dx.doi.org/10.2174/1381612811319260008
DOI https://dx.doi.org/10.2174/1381612811319260008 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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