title: Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.
abstract: We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.
authors.affiliation: Fox Chase Chemical Diversity Center, Inc, 3805 Old Easton Road, Doylestown, PA 18902, United States.
authors.forename: H Marie
authors.initials: HM
authors.lastname: Loughran
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Han
authors.affiliation: Fox Chase Chemical Diversity Center, Inc, 3805 Old Easton Road, Doylestown, PA 18902, United States.
authors.forename: Jay E
authors.initials: JE
authors.lastname: Wrobel
authors.affiliation: Fox Chase Chemical Diversity Center, Inc, 3805 Old Easton Road, Doylestown, PA 18902, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Decker
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Harty
authors.affiliation: Fox Chase Chemical Diversity Center, Inc, 3805 Old Easton Road, Doylestown, PA 18902, United States.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D029043:Ebolavirus / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D029024:Marburgvirus / Q000737:chemistry; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects*; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D011810:Quinoxalines; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Antiviral therapeutic; Budding; Ebola virus; L-domain; Marburg virus; Nedd4; PPxY; RNA viruses; Virus egress