Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus.
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.
Gu
Baohua
B
Drexel Institute for Biotechnology and Virology Research, Drexel University, College of Medicine, Doylestown, PA, USA. baohua.gu@drexel.edu
Mason
Peter
P
Wang
Lijuan
L
Norton
Pamela
P
Bourne
Nigel
N
Moriarty
Robert
R
Mehta
Anand
A
Despande
Mehendra
M
Shah
Rajendra
R
Block
Timothy
T
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*
D000998:Antiviral Agents