Inhibition of cellular STAT3 synergizes with the cytomegalovirus kinase inhibitor maribavir to disrupt infection.
Therapeutic strategies controlling human cytomegalovirus (hCMV) infection are limited due to adverse side effects and emergence of antiviral resistance variants. A compound being evaluated for treating hCMV disease is maribavir (MBV) which disrupts replication by inhibiting the viral kinase pUL97. Previous studies have demonstrated that the antiviral activity of MBV is sensitive to the proliferation state of the infected cell. In these studies, we were interested in determining whether inhibition of the pro-proliferative transcription factor, signal transducer and activator of transcription-3 (STAT3), could influence the antiviral activity of MBV. The addition of the STAT3 inhibitor, S3i-201, during infection altered hCMV-mediated changes in cell cycle protein expression. Upon combining S3i-201 with MBV, our data suggest that STAT3 inhibition is acting synergistically with MBV to inhibit infection in vitro. Furthermore, specific concentrations of S3i-201 and MBV induced caspase-dependent death of infected but not uninfected cell. Our studies suggest that treating infection with both S3i-201 and MBV is a novel approach to inhibit hCMV replication.
Department of Microbiology and Molecular Genetics, Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Justin M
JM
Reitsma
Scott S
SS
Terhune
D000636:Aminosalicylic Acids / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D012263:Ribonucleosides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
D000636:Aminosalicylic Acids; D000998:Antiviral Agents; D001557:Benzenesulfonates; D001562:Benzimidazoles; D012263:Ribonucleosides; D050796:STAT3 Transcription Factor; C520337:NSC 74859; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole
HCMV; Human cytomegalovirus; Maribavir; STAT3; STAT3 inhibitor; UL97