title: HIV-1 associated Topoisomerase IIβ kinase: a potential pharmacological target for viral replication.
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.
authors.affiliation: Department of Biotechnology, School of Life Sciences, University of Hyderabad, India
authors.forename: Kannapiran
authors.initials: K
authors.lastname: Ponraj
authors.forename: Maddela
authors.initials: M
authors.lastname: Prabhakar
authors.forename: R S
authors.initials: RS
authors.lastname: Rathore
authors.forename: Akhila
authors.initials: A
authors.lastname: Bommakanti
authors.forename: Anand K
authors.initials: AK
authors.lastname: Kondapi
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D004268:DNA-Binding Proteins; D011725:Pyridines; D004250:DNA Topoisomerases, Type II