title: Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses.
abstract: Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2(cycl), an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2(cycl) and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry.
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Carney
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, United States.
authors.forename: Christian D S
authors.initials: CD
authors.lastname: Nelson
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
authors.forename: Bennett D
authors.initials: BD
authors.lastname: Ferris
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Stevens
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Lipovsky
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States.
authors.forename: Teymur
authors.initials: T
authors.lastname: Kazakov
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: DiMaio
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, United States.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Atwood
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States. Electronic address: jason_sello@brown.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sello
mesh_terms: D001370:Axonal Transport / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007577:JC Virus / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000821:virology*; D027383:Papillomaviridae / Q000187:drug effects* / Q000502:physiology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D011799:Quinazolines
keywords: Dihydroquinazolinone; Papillomavirus; Polyomavirus; Retrograde trafficking; SAR
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