title: Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses.
abstract: Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902, United States. jinhong.chang@drexelmed.edu
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.forename: Xuesen
authors.initials: X
authors.lastname: Zhao
authors.forename: Tina
authors.initials: T
authors.lastname: Gill
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Comunale
authors.forename: Yanming
authors.initials: Y
authors.lastname: Du
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Alonzi
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
authors.forename: Andrea
authors.initials: A
authors.lastname: Cuconati
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D029043:Ebolavirus / Q000187:drug effects / Q000472:pathogenicity; D004721:Endoplasmic Reticulum / Q000201:enzymology; D065089:Glycoside Hydrolase Inhibitors; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D006801:Humans; D050111:Imino Sugars / Q000493:pharmacokinetics / Q000494:pharmacology*; D008379:Marburg Virus Disease / Q000188:drug therapy; D029024:Marburgvirus / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases
chemical_list: D000998:Antiviral Agents; C585142:CM-10-18 compound; D065089:Glycoside Hydrolase Inhibitors; C000600715:IHVR-11029; C000600716:IHVR-17028; D050111:Imino Sugars; C042059:glucosidase I; D000520:alpha-Glucosidases