Differences between experimental groups were considered significant at P values of <0.05. The imino sugars, represented by Zavesca (miglustat or NBDNJ) and Glyset (miglitol), the drugs approved for the treatment of Type II Diabetes and Type 1 Gaucher’s disease (EMEA, 2003), consist of a DNJ head group and an alkyl side chain off the nitrogen of the head ring.
Although it has been extensively demonstrated that imino sugars inhibited the variety of enveloped viruses in cultured cells, their in vivo antiviral efficacies have thus far only been demonstrated in mice infected with DENV or Japanese encephalitis virus ( Schul et al., 2007 and Wu et al., 2002). In order to develop imino sugars for the treatment of VHFs, we modified CM-10-18, a pharmacophore with in vitro and in vivo antiviral activities against DENV Selleck Cabozantinib ( Chang et al., 2011a, Chang et al., 2011b and Chang et al., 2009), Trichostatin A manufacturer to further improve its antiviral potency and pharmacological properties. The novel derivatives were synthesized with combinations of heteroatom variations and alterations of terminal structures on the
alkyl side chain ( Fig. 1). Total of 120 derivatives of CM-10-18 were synthesized and screened for their antiviral potency against BVDV and DENV of the Flaviviridae and TCRV of the Arenaviridae as well as cytotoxicity. Twenty-four compounds with superior antiviral activities were selected for an ADME profiling ( Yu et al., 2012). Three lead compounds, were nominated based on their structural diversification, antiviral potency, cytotoxicity and ADME profiles ( Table 1 and Table 2). These are: IHVR11029 ((2R,3R,4R,5S)-1-(6-(2,5-difluorophenoxy)hexyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, phenylether DNJ), IHVR17028 (N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide,
pivalamide DNJ) and IHVR19029 (3-(tert-butyl)-1-cyclohexyl-1-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)urea, tert-butyl urea DNJ). Table 1 summaries the antiviral activity against BVDV, TCRV and DENV as determined by virus yield reduction assays, as well as cytotoxicity as determined by MTT assays, all three compounds demonstrated a broad-spectrum antiviral activity in cell cultures and increased potency compared Celastrol to their parental compound, CM-10-18. Next, antiviral spectrum and activity of the three lead imino sugars were tested against representative hemorrhagic fever viruses from all four viral families that cause VHFs. As shown in Fig. 2, in addition to surrogate viruses (BVDV and TCRV) and DENV tested in SAR study and lead optimization, these compounds also dose-dependently inhibited RVFV of the Bunyaviridae in a yield reduction assay. Furthermore, the compounds dose-dependently suppressed the assembly/secretion of EBOV and LASV envelope glycoprotein (G) pseudotyped lentiviral particles, suggesting the maturation of the viral glycoproteins was inhibited by the compounds.