Identification of human adenovirus replication inhibitors from a library of small molecules targeting cellular epigenetic regulators

Abstract

Human adenovirus (HAdV) can cause severe disease in certain at-risk populations such as newborns, the elderly and those with compromised immune systems. Unfortunately, no FDA-approved anti-HAdV drug is currently available for treatment. Within the nucleus of infected cells, the HAdV genome associates with histones and forms a chromatin-like structure during early infection, and viral gene expression appears regulated by cellular epigenetic processes. Thus, one potential therapeutic strategy to combat HAdV disease may be to target the cellular proteins involved in modifying the viral nucleoprotein structure and facilitating HAdV gene expression and replication. We have screened a panel of small molecules that modulate the activity of epigenetic regulatory proteins for compounds affecting HAdV gene expression. Several of the compounds, specifically chaetocin, gemcitabine and lestaurtinib, reduced HAdV recovery by 100- to 1000-fold, while showing limited effect on cell health, suggesting that these compounds may indeed be promising as anti-HAdV therapeutics.

Recent Advances in Novel Antiviral Therapies against Human Adenovirus

“…Another anti-HIV agent, stavudine (a thymidine analogue) was also found to be potent against HAdV [124]. Furthermore, we observed that gemcitabine, a cytidine analogue and a chemotherapeutic agent, abrogates gene expression and the replication of HAdV-4, HAdV-5 and HAdV-7 [126], while cytarabine led to modest effects on HAdV-5 gene expression and yield [127]. These compounds may prove to be useful in cases where cidofovir fails to improve disease outcome, but thorough assessment of their efficacy and safety in animal models is required prior to clinical testing.…”

“…Nucleoside/nucleotide analogues Zalcitabine [118,122,123] Alvoudine [118] Stavudine [124] Acyclic nucleoside phosphonate analogues of cidofovir [118] Various ether lipid-ester prodrugs of cidofovir [125] Gemcitabine [126] Cytarabine [127] Other nucleoside/nucleotide analogues [128] Inhibitors of epigenetic regulators…”

“…Valproic acid [129] Vorinostat [130] Trichostatin A [130] Other HDAC inhibitors [130] Chaetocin [126] GSK126 [131] GSK343 [131] Lestaurtinib [126] Steroid-based compounds Digoxin [127,132] Digitoxin [132] Digitoxigenin [127] Lanatoside C [127] Dexamethasone [127] Flunisolide [127] Mifepristone [133] Epiandrosterone and derivatives [134] Other compounds…”

“…Interestingly, HDAC inhibitors can suppress LSD1 activity [150], which may contribute to their anti-HAdV properties. We also recently discovered that chaetocin (primarily inhibits the H3K9 methyltransferases SUV39H1 and G9a/GLP) and lestaurtinib (inhibits JAK2 and PRK1, which can phosphorylate residues on H3 in addition to other cellular targets) are potent inhibitors of viral gene expression and DNA replication that can lead to a~100-fold reduction in the virus yield in cell culture [126]. Further studies are required to determine whether these latter compounds exert their effect through epigenetic means or through some other mechanism.…”

“…However, the majority of new HAdV inhibitors have been identified through investigations on a single or a handful of select compounds [132,133,136,137]. To date, very few drug library screens have been performed to find novel anti-HAdV compounds [126,127,135,[169][170][171]. Many of these screens were conducted using non-replicating HAdV vectors that expressed the green fluorescent protein (GFP) from a heterologous promoter, which may not accurately mimic wild-type virus gene expression and replication [135,171].…”