TY - JOUR
T1 - A study of the Topoisomerase II activity in HIV-1 replication using the ferrocene derivatives as probes
AU - Kondapi, Anand K.
AU - Satyanarayana, Nathamu
AU - Saikrishna, A. D.
N1 - Funding Information:
We thank the Council of Industrial Research, India for providing doctoral fellowship to N.S. and A.D.S.K. We thank the reagent contributors of the NIH AIDS research reference reagent program for providing the materials required for the work.
PY - 2006/6/15
Y1 - 2006/6/15
N2 - Human Topoisomerase II is present in two isoforms, 170 KDa α and 180 KDa β. Both the isoforms play a crucial role in maintenance of topological changes during DNA replication and recombination. It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication. In the present study, we have studied the molecular action of Topoisomerase II inhibitors, azalactone ferrocene (AzaFecp), Thiomorpholide amido methyl ferrocene (ThioFecp), and Ruthenium benzene amino pyridine (Ru(ben)Apy) on cell proliferation and also on various events of HIV-1 replication cycle. The Topoisomerase II β over-expressing neuroblastoma cell line shows a higher sensitivity to these compounds compared to the Sup-T1 cell line. All the three Topoisomerase II inhibitors show significant anti-HIV activity at nanomolar concentrations against an Indian isolate of HIV-193IN101 in Sup-T1 cell line. An analysis of action of these compounds on proviral DNA synthesis at 5 h of post-infection shows that they inhibit proviral DNA synthesis as well as the formation of pre-integration complexes completely. Further analysis, using polymerase chain reaction and western blot, showed that both the Topoisomerase II α and β isoforms are present in the pre-integration complexes, suggesting their significant role in HIV-1 replication.
AB - Human Topoisomerase II is present in two isoforms, 170 KDa α and 180 KDa β. Both the isoforms play a crucial role in maintenance of topological changes during DNA replication and recombination. It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication. In the present study, we have studied the molecular action of Topoisomerase II inhibitors, azalactone ferrocene (AzaFecp), Thiomorpholide amido methyl ferrocene (ThioFecp), and Ruthenium benzene amino pyridine (Ru(ben)Apy) on cell proliferation and also on various events of HIV-1 replication cycle. The Topoisomerase II β over-expressing neuroblastoma cell line shows a higher sensitivity to these compounds compared to the Sup-T1 cell line. All the three Topoisomerase II inhibitors show significant anti-HIV activity at nanomolar concentrations against an Indian isolate of HIV-193IN101 in Sup-T1 cell line. An analysis of action of these compounds on proviral DNA synthesis at 5 h of post-infection shows that they inhibit proviral DNA synthesis as well as the formation of pre-integration complexes completely. Further analysis, using polymerase chain reaction and western blot, showed that both the Topoisomerase II α and β isoforms are present in the pre-integration complexes, suggesting their significant role in HIV-1 replication.
KW - Anti proliferation
KW - Anti-HIV activity
KW - Ferrocene derivatives
KW - HIV infection
KW - Organometallic compounds
KW - Proviral DNA
KW - Ruthenium derivatives
KW - Topoisomerase II poisons
KW - Topoisomerase II α
KW - Topoisomerase II β
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U2 - 10.1016/j.abb.2006.04.003
DO - 10.1016/j.abb.2006.04.003
M3 - Article
C2 - 16712776
AN - SCOPUS:33746887446
SN - 0003-9861
VL - 450
SP - 123
EP - 132
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -