Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses

Abstract

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.

Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals

“…Iminosugars, glycomimetics originally isolated from plants, represent a promising class of ERQC inhibitors that are well tolerated in mammals (13). Altering glycoprotein processing via inhibition of the ER α-GluI and α-GluII by iminosugars has demonstrated in vitro and in vivo efficacy against multiple virus families (14, 15), including Herpes-, Hepadna-, Toga-, Rhabdo-, Orthomyxo-, Paramyxo-and Retroviridae, as well as those virus families that cause hemorrhagic fever (16,17), including Arena-, Flavi-and Filoviridae. The deoxynojirimycin iminosugar derivative N-9′-methoxynonyl 1-deoxynojirimycin (MON-DNJ) has antiviral activity in vivo, against both dengue virus (18) and influenza A (H1N1) (19) and influenza B (17), with the Significance Most pathogenic enveloped viruses crucially depend on the quality control (QC) machinery in the endoplasmic reticulum (ER) of the host cell.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…ER α-glucosidases I and II play a critical role in glycosylation of viral proteins 102 . Inhibition of ER α-glucosidases has shown to affect viral particle assembly and/or secretion of HBV, HIV, HSV-1, influenza virus, parainfluenza virus, measles virus (MV), MARV, EBOV, HCV and other members of the Flaviviridae, such as bovine viral diarrhea virus (BVDB), DENV, WNV, and japanese encephalitis virus (JEV) 117 . Celgosivir has been proven effective against HCV and DENV infections in vitro and in vivo 118,119 .…”

“…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.…”

Vesicular stomatitis virus (VSV) as a paradigm for predicting antiviral activity against Ebola virus (EBOV)

“…Endoplasmic reticulum (ER) glucosidase inhibitors The imino sugar 1-deoxynojirimycin is a glucose mimic, with a nitrogen atom replacing the oxygen, that inhibits the ER α-glucosidases I and II, which are essential in the maturation of viral envelope glycoproteins (64). Its derivatives IHVR11029, IHVR17028 and IHVR19029 were shown to protect mice against the mortality of Marburg and EBOV infections (65). Benzylpiperazine adamantane diamides EBOV entry into the host cells requires the cholesterol transporter Niemann-Pick C1 (66), and this process can be blocked by benzylpiperazine adamantane diamides (67).…”