Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus

Baohua Gu, Peter Mason, Lijuan Wang, Pamela Norton, Nigel Bourne, Robert Moriarty, Anand Mehta, Mehendra Despande, Rajendra Shah, Timothy Block

Research output: Contribution to journalArticle

43 Citations (Scopus)

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-95II), led to a structure that was as well tolerated as DNJ (CC 50>500 μM), 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.

Original languageEnglish (US)
Pages (from-to)49-59
Number of pages11
JournalAntiviral Chemistry and Chemotherapy
Volume18
Issue number1
StatePublished - 2007

Fingerprint

Bovine Viral Diarrhea Viruses
West Nile virus
Dengue Virus
Hepatitis B virus
Antiviral Agents
Viruses
Morphogenesis
Endoplasmic Reticulum
Hydroxyl Radical
Flaviviridae
Glucosidases
Virus Release
Poisons
Hepacivirus
Ether
Polysaccharides
Nitrogen
Carbon
Oxygen
Enzymes

Keywords

  • Bovine viral diarrhea virus
  • Dengue virus
  • Deoxynojirimycin
  • Hepatitis B virus
  • West Nile virus

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus. / Gu, Baohua; Mason, Peter; Wang, Lijuan; Norton, Pamela; Bourne, Nigel; Moriarty, Robert; Mehta, Anand; Despande, Mehendra; Shah, Rajendra; Block, Timothy.

In: Antiviral Chemistry and Chemotherapy, Vol. 18, No. 1, 2007, p. 49-59.

Research output: Contribution to journalArticle

Gu, B, Mason, P, Wang, L, Norton, P, Bourne, N, Moriarty, R, Mehta, A, Despande, M, Shah, R & Block, T 2007, 'Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus', Antiviral Chemistry and Chemotherapy, vol. 18, no. 1, pp. 49-59.
Gu, Baohua ; Mason, Peter ; Wang, Lijuan ; Norton, Pamela ; Bourne, Nigel ; Moriarty, Robert ; Mehta, Anand ; Despande, Mehendra ; Shah, Rajendra ; Block, Timothy. / Antiviral profiles of novel iminocyclitol compounds against bovine viral diarrhea virus, West Nile virus, dengue virus and hepatitis B virus. In: Antiviral Chemistry and Chemotherapy. 2007 ; Vol. 18, No. 1. pp. 49-59.
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