title: Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus.
abstract: The antiviral activity of iminocyclitol compounds with a deoxynojirimycin (DNJ) head group and either a straight chain alkyl or alkylcycloalkyl group attached to the nitrogen atom have been tested in vitro against multiple-enveloped viruses. Several of these analogues were superior to previously reported DNJ compounds. Iminocyclitols that inhibit the glycan-processing enzyme endoplasmic-reticular glucosidase have been shown to inhibit the morphogenesis of viruses that bud from the endoplasmic reticulum (ER) at non-cytotoxic concentrations. Bovine viral diarrhoea virus (BVDV) has been used as a surrogate system for study of the hepatitis C virus, which belong to the virus family (Flaviviridae) as West Nile virus (WNV) and dengue virus (DV). N-Nonyl-DNJ (NNDNJ) was previously reported to have micromolar antiviral activity against BVDV, but a limiting toxicity profile. N-Butylcyclohexyl-DNJ (SP169) was shown to be as potent as NNDNJ in assays against BVDV and less toxic. However, it was inactive against hepatitis B virus (HBV). The present study reports efforts to improve the performance profiles of these compounds. Introduction of an oxygen atom into the N-alkyl side chain of DNJ, either as an ether or a hydroxyl functionality, reduced toxicity but sacrificed potency. Introduction of a hydroxyl group at the tertiary carbon junction of the cycloalkyl and linear alkyl group, as in N-pentyl-(1-hydroxycyclohexyl)-DNJ (OSL-9511), led to a structure that was as well tolerated as DNJ (CC50>500 microM), but retained micromolar antiviral activity against all ER morphogenesis budding viruses tested: BVDV, WNV, DV and HBV. The implication of this modification to the development of broad-spectrum antiviral agents is discussed.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Drexel University, College of Medicine, Doylestown, PA, USA. baohua.gu@drexel.edu
authors.forename: Baohua
authors.initials: B
authors.lastname: Gu
authors.forename: Peter
authors.initials: P
authors.lastname: Mason
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Pamela
authors.initials: P
authors.lastname: Norton
authors.forename: Nigel
authors.initials: N
authors.lastname: Bourne
authors.forename: Robert
authors.initials: R
authors.lastname: Moriarty
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
authors.forename: Mehendra
authors.initials: M
authors.lastname: Despande
authors.forename: Rajendra
authors.initials: R
authors.lastname: Shah
authors.forename: Timothy
authors.initials: T
authors.lastname: Block
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects*; D030241:Diarrhea Virus 1, Bovine Viral / Q000187:drug effects*; D030242:Diarrhea Virus 2, Bovine Viral / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents