ihvr-11029 and Dengue

Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.

Topics: alpha-Glucosidases; Animals; Antiviral Agents; Dengue; Dogs; Drug Evaluation, Preclinical; Ebolavirus; Endoplasmic Reticulum; Glycoside Hydrolase Inhibitors; HEK293 Cells; Hemorrhagic Fever, Ebola; Humans; Imino Sugars; Marburg Virus Disease; Marburgvirus; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).

Topics: 1-Deoxynojirimycin; alpha-Glucosidases; Animals; Antiviral Agents; Biological Availability; Cattle; Cell Line; Cricetinae; Dengue; Dengue Virus; Diarrhea Viruses, Bovine Viral; Glycoside Hydrolase Inhibitors; Humans; Male; Microbial Sensitivity Tests; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Viral Envelope Proteins; Virus Replication