Targeting Cell Division Cycle 25 Homolog B To Regulate Influenza Virus Replication

Abstract

bInfluenza virus is a worldwide global health concern causing seasonal morbidity mortality and economic burden. Chemotherapeutics is available; however, rapid emergence of drug-resistant influenza virus strains has reduced its efficacy. Thus, there is a need to discover novel antiviral agents. In this study, RNA interference (RNAi) was used to screen host genes required for influenza virus replication. One pro-influenza virus host gene identified was dual-specificity phosphatase cell division cycle 25 B (CDC25B). RNAi screening of CDC25B resulted in reduced influenza A virus replication, and a CDC25B small-molecule inhibitor (NSC95397) inhibited influenza A virus replication in a dose-dependent fashion. Viral RNA synthesis was reduced by NSC95397 in favor of increased beta interferon (IFN-␤) expression, and NSC95397 was found to interfere with nuclear localization and chromatin association of NS1, an influenza virus protein. As NS1 has been shown to be chromatin associated and to suppress host transcription, it is likely that CDC25B supports NS1 nuclear function to hijack host transcription machinery in favor of viral RNA synthesis, a process that is blocked by NSC95397. Importantly, NSC95397 treatment protects mice against lethal influenza virus challenge. The findings establish CDC25B as a pro-influenza A virus host factor that may be targeted as a novel influenza A therapeutic strategy.

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease

“…It has been reported to modulate the expression of immune molecules and to have anticancerogenic effects [ 51 , 52 ]. NSC95397 has also been shown to have antiviral effects, as it has been associated with increased interferon beta production and reduced growth of Influenza virus in mouse models [ 53 ]. Although NSC95397 inhibited nsp15 activity in vitro , it did not impair the proliferation of SARS-CoV-2 in VERO E6 cells, which are a commonly used host cells for viral growth under laboratory conditions.…”

Repurposing Kinase Inhibitors as Antiviral Agents to Control Influenza A Virus Replication

“…Other reports also demonstrated the role of CDK and its activating phosphatase CDC25B for the phosphorylation of viral NS1 protein, which is important for antagonism of host antiviral response and efficient virus replication. 47,48 While the role of DNA-PK during influenza virus infection is yet understood, the role of PI3K signaling pathway during influenza virus replication has been described in numerous reports. PI3K activation is induced early during influenza virus infection for virus entry and viral ribonucleoprotein export from the nucleus, while it also acts to block premature apoptosis.…”

An integrative sparse boosting analysis of cancer genomic commonality and difference

“…It is involved in cell cycle progression, chromatin modulation, and transcriptional regulation. 28 CDC25 is a candidate prognostic marker and therapeutic target not only for AML but also for other types of cancers. 29 Adenosine deaminase 1 (ADA) has been found to be a diagnostic and prognostic marker for patients with acute lymphoblastic leukemia.…”