HIV-1 associated Topoisomerase IIβ kinase: a potential pharmacological target for viral replication

Curr Pharm Des. 2013;19(26):4776-86. doi: 10.2174/1381612811319260008.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Catalytic Domain
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / isolation & purification
  • DNA Topoisomerases, Type II / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / isolation & purification
  • DNA-Binding Proteins / metabolism*
  • HIV-1 / enzymology*
  • Phosphorylation
  • Pyridines / pharmacology
  • Virus Replication / drug effects*

Substances

  • Anti-HIV Agents
  • DNA-Binding Proteins
  • Pyridines
  • DNA Topoisomerases, Type II