title: Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo.
abstract: Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, United States. jinhong.chang@drexelmed.edu
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Andy
authors.initials: A
authors.lastname: Yip
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Dominic
authors.initials: D
authors.lastname: Alonzi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Reinkensmeier
authors.forename: Xiaoben
authors.initials: X
authors.lastname: Pan
authors.forename: Xiaowang
authors.initials: X
authors.lastname: Qu
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Weidner
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.forename: Nigel
authors.initials: N
authors.lastname: Borune
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kinch
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Rayahin
authors.forename: Robert
authors.initials: R
authors.lastname: Moriarty
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D012254:Ribavirin / Q000008:administration & dosage* / Q000494:pharmacology; D014766:Viremia / Q000517:prevention & control
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D012254:Ribavirin