title: Design, synthesis, and evaluation of WC5 analogues as inhibitors of human cytomegalovirus Immediate-Early 2 protein, a promising target for anti-HCMV treatment.
abstract: Although human cytomegalovirus (HCMV) infection is mostly asymptomatic for immunocompetent individuals, it remains a serious threat for those who are immunocompromised, in whom it is associated with various clinical manifestations. The therapeutic utility of the few available anti-HCMV drugs is limited by several drawbacks, including cross-resistance due to their common mechanism of action, i.e., inhibition of viral DNA polymerase. Therefore, compounds that target other essential viral events could overcome this problem. One example of this is the 6-aminoquinolone WC5, which acts by directly blocking the transactivation of essential viral Early genes by the Immediate-Early 2 (IE2) protein. In this study, the quinolone scaffold of the lead compound WC5 was investigated in depth, defining more suitable substituents for each of the scaffold positions explored and identifying novel, potent and nontoxic compounds. Some compounds showed potent anti-HCMV activity by interfering with IE2-dependent viral E gene expression. Among them, naphthyridone 1 was also endowed with potent anti-HIV activity in latently infected cells. Their antiviral profile along with their innovative mechanism of action make these anti-HCMV quinolones a very promising class of compounds to be exploited for more effective antiviral therapeutic treatment.
authors.affiliation: Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mercorelli
authors.forename: Luca
authors.initials: L
authors.lastname: Sancineto
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gribaudo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000188:drug therapy; D015195:Drug Design; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015363:Quinolones; D015534:Trans-Activators; C586457:WC5 compound
keywords: 6-aminoquinolones; HCMV; antiviral agents; immediate-early 2 protein; inhibitors