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Impact of RNA polymerase I inhibitor CX-5461 on viral kinase-dependent and -independent cytomegalovirus replication. Antiviral Res 2018 05;153:33-38

Date

02/20/2018

Pubmed ID

29458130

Pubmed Central ID

PMC6015744

DOI

10.1016/j.antiviral.2018.02.014

Scopus ID

2-s2.0-85043578832   8 Citations

Abstract

Human cytomegalovirus (HCMV) infections cause congenital birth defects and disease in immunosuppressed individuals. Antiviral compounds can control infection yet their use is restricted due to concerns of toxicity and the emergence of drug resistant strains. We have evaluated the impact of an RNA Polymerase I (Pol I) inhibitor, CX-5461 on HCMV replication. CX-5461 inhibits Pol I-mediated ribosomal DNA transcription by binding G-quadruplex DNA structures and also activates cellular stress response pathways. The addition of CX-5461a??at both early and late stages of the HCMV infection inhibited viral DNA synthesis and virus production. Interestingly, adding CX-5461 after the onset of viral DNA synthesis resulted in a greater reduction compared to continuous treatment starting early during infection. We observed an accompanying increase in cyclin-dependent kinase inhibitor p21 in infected cells treated late but not early which likely explains the differences. Our previous studies demonstrated the importance of p21 in the antiviral activity of the HCMV kinase inhibitor, maribavir. Addition of CX-5461 increased the anti-HCMV activity of maribavir. Our data demonstrate that CX-5461 inhibits HCMV replication and synergizes with maribavir to disrupt infection.

Author List

Westdorp KN, Terhune SS

Author

Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antiviral Agents
Benzimidazoles
Benzothiazoles
Cell Line
Cytomegalovirus
Drug Synergism
Fibroblasts
Humans
Microbial Sensitivity Tests
Naphthyridines
RNA Polymerase I
Ribonucleosides
Virus Replication