The effect of oral treatment with 6-O-butanoyl castanospermine (MDL 28,574) in the murine zosteriform model of HSV-1 infection

Abstract

Oral treatment of mice, cutaneously infected with herpes simplex virus type 1 (HSV-1) (strain SC16), with the alpha-glucosidase 1 inhibitor 6-O-butanoyl castanospermine (MDL 28,574) produced a significant delay in lesion development and reduced the amount of virus recovered from the brain. Virus load in the brains of mice, whose treatment started 2 days prior to infection, was reduced approximately 100-fold when compared to untreated controls. Treatment initiated at the time of infection, while less effective than pre-treatment, nevertheless reduced virus recovery from the brain by 10-fold. Consistent with its antiviral activity, orally administered MDL 28,574 was rapidly incorporated by brain tissue and mice fed with compound over extended periods maintained relatively high levels of drug at this site.

Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses

“…Thus, it has been reasoned that inhibition of ␣-glucosidases might disturb the maturation, secretion, and function of viral envelope glycoproteins and, as a result, inhibit viral particle assembly and/or secretion of enveloped viruses. Consistent with this notion is the observation that for many types of enveloped viruses, including hepatitis B virus, human immunodeficiency virus (HIV), herpes simplex virus type 1, influenza viruses, parainfluenza virus, and measles virus, as well as several members of the Flaviviridae family, such as bovine viral diarrhea virus (BVDV), dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus, and hepatitis C virus (HCV), virion production can be inhibited by ␣-glucosidase inhibitors, such as DNJ and its derivatives (3,5,6,9,14,17,22,30,31,34). For some viruses, virion particles produced under treatment with glucosidase inhibitors carried unprocessed (or altered) glycans on their envelope glycoproteins and were reduced in infectivity (17,26).…”

Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo

“…The compound is water soluble and can be readily isolated in large quantity through a rather simple purification scheme (37). In cells, castanospermine acts as an ER ␣-glucosidase I inhibitor and reduces infection of a subset of enveloped RNA and DNA viruses in vitro (DEN [6,[49][50][51][52], and influenza virus [15,38]) and in vivo (herpes simplex virus [5] and Rauscher murine leukemia virus [40]). Studies of its mechanism of action suggest that castanospermine may disrupt folding of some viral proteins by preventing the removal of the terminal glucose residue on N-linked glycans.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…CST, its derivative celgosivir (6 O-butanoyl castanospermine) and DNJ have been described to inhibit the replication of multiple viruses both in vitro and in vivo [117][118][119][187][188][189][190][191][192][193][194][195][196][197] (Table 2). In mammalian cells both compounds block the function of ER α-glucosidases I and II.…”

“…Still, whether CV-N has a binding partner in the host has not been determined yet and further studies are needed to assess the safety of CV-N as a therapeutic drug. HSV-2 EC50 < 4µM in plaque assay 190,191 HIV 100 µg/mL 100% syncitia inhibition in H9 and CD4-Jurkat cells 188,199,229,230 Lantibiotics are peptides with unusual amino acids produced by several gram-positive bacteria 249,250 . Labyrinthopeptin A1 (LabyA1) (16) belongs to a novel class of carbacyclic lantibiotics 251 , 252 that was isolated from the actinomycete Actinomadura namibiensis.…”