Impact of RNA polymerase I inhibitor CX-5461 on viral kinase-dependent and -independent cytomegalovirus replication. Antiviral Res 2018 May;153:33-38
Date
02/20/2018Pubmed ID
29458130Pubmed Central ID
PMC6015744DOI
10.1016/j.antiviral.2018.02.014Scopus ID
2-s2.0-85043578832 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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-5461 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 SSAuthor
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antiviral AgentsBenzimidazoles
Benzothiazoles
Cell Line
Cytomegalovirus
Drug Synergism
Fibroblasts
Humans
Microbial Sensitivity Tests
Naphthyridines
RNA Polymerase I
Ribonucleosides
Virus Replication