Antiviral activity of (+)-rutamarin against Kaposi's sarcoma-associated herpesvirus by inhibition of the catalytic activity of human topoisomerase II.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection.

• Authors: Bo Xu, Ling Wang, Lorenzo González-Molleda, Yan Wang, Jun Xu, Yan Yuan
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 1 Pg. 563-73 ( 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24295975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antiviral Agents
• Benzopyrans
• DNA-Binding Proteins
• rutamarin
• DNA Topoisomerases, Type II

Topics

• Antigens, Neoplasm (metabolism)
• Antiviral Agents (pharmacology)
• Benzopyrans (pharmacology)
• DNA Topoisomerases, Type II (metabolism)
• DNA-Binding Proteins (metabolism)
• Humans
• Sarcoma, Kaposi (virology)
• Virus Replication (drug effects)