Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents

Abstract

Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

Keywords: Ebola; Marburg; antivirals; filovirus; glucosidase inhibitors; imino sugars; therapeutics.

Figure 1

Glucosidase mediated steps in the N-linked glycosylation pathway. The pathway of N-linked glycosylation at asparagine of nascent polypeptides is shown. Polypeptides synthesized by translation in the ER are shown as the ribbon line (black) as unfolded, with the unprocessed 3-glucose terminal containing ‘lollipop' oligosaccharide structure, attached at an asparagine. The terminal glucose and second to terminal glucoses (Glu) of this oligosaccharide is removed processively by ER resident, membrane bound, glucosidases I and II. Following removal of these glucose molecules, the protein chaperon, Calnexin, mediates folding of the polypeptide, which is then transported to the Golgi and further processed for secretion. Inhibition of ER glucosidases prevents polypeptide interaction with Calnexin and results in polypeptide misfolding, retention and/or degradation.

Figure 2

Modifications of the imino sugar NBDNJ that greatly improve antiviral activity but not enzyme inhibitory activity. The imino sugar NBDNJ is a butylated DNJ with millimolar antiviral activity in vitro. Alterations of its side chain as represented in compounds CM-10-18 and IHVR-19029, improve antiviral activity by up to 1000-fold, but only modestly improve enzyme inhibition. This is presumably because the improvements are largely related to cell access. See text. ND, not done.