title: Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication.
abstract: New targets for antiviral strategies are needed against human cytomegalovirus (HCMV), a major human pathogen. A cell-based screen aimed at finding inhibitors of the viral transcription factor Immediate-Early 2 (IE2) was performed in HCMV-infected cells expressing EGFP under the control of an IE2-inducible viral promoter. Screening of a library of bioactive small molecules led to the identification of several compounds able to inhibit EGFP expression and also HCMV replication with potency in the low-micromolar range. Follow-up studies with four selected hits indicated that they all block viral DNA synthesis as well as viral Early and Late gene expression. Furthermore, mechanistic studies confirmed that the compounds specifically act via inhibition of IE2 transactivating activity, thus blocking viral Early gene expression and the progression of virus replication. These results provide proof of concept for identifying small molecules that modulate the activity of a microbial transcription factor to control pathogen replication.
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mercorelli
authors.affiliation: Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Luganini
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Nannetti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gribaudo
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121 Padua, Italy. Electronic address: arianna.loregian@unipd.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development*; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D005434:Flow Cytometry; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004279:DNA, Viral; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D054852:Small Molecule Libraries; D015534:Trans-Activators