Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

Abstract

Endoplasmic reticulum (ER)-resident α-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER α-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER α-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention.

N-linked sugar-regulated protein folding and quality control in the ER

“…To understand how these respond to variation in the quantity and the quality of the cargo load is crucial for designing therapeutic strategies for diseases caused by production, accumulation or destruction of aberrant polypeptides or to intervene to contrast infection by pathogens that exploit the host cell protein factory during their infection cycle. For instance, one strategy has been the use of α-glucosidase I and II inhibitors to inhibit viral infectivity (149) based on the findings that viral glycoproteins are more dependent on CNX/CRT assistance for folding than cellular proteins (63). Inhibiting glucosidase trimming prevents the entry of viral proteins into the CNX/CRT cycle (150).…”

“…Derivatives of the iminosugars castanospermine and deoxynojirmycin have been widely used to inhibit the infectivity of a vast range of both DNA and RNA viruses. Some of these inhibitors have entered clinical trials (149). Optimization of the lectin chaperone pathway may also help to correct the folding of defective proteins associated with loss of function diseases (96) or increase the expression of recombinant proteins used as therapeutics.…”

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

“…Traditionally, virus-encoded enzymes have been the primary antiviral targets (54)(55)(56). However, nonenzymatic viral structural and nonstructural proteins have now been demonstrated to be viable targets of highly selective and potent antiviral agents, as highlighted by the FDA approval of HCV NS5A inhibitors for treatment of chronic hepatitis C (57) as well as the development of antiviral agents against distinct nonstructural proteins of many other RNA viruses (58).…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…Viruses also hijack host factors involved in protein folding such as cyclophilin A and endoplasmic reticulum (ER)-associated α-glucosidases 102 . Cyclophilin A (CypA) belongs to the family of peptidyl-prolyl-cis-trans isomerases (PPIase) and is involved in protein folding, trafficking, formation of multiprotein complexes (MPC) and other cellular functions 103,104 .…”

“…Alisporivir (Debio-025) and SCY-635, both CsA analogues, have shown antiviral activity against HCV in vivo and are currently in combination with other anti-HCV compounds in various clinical trials 115,116 . 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 .…”