Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo

Abstract

Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER α-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER α-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER α-glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1-2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-α-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR-19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents.

A new dinuclear copper (II) complex of 2,5–Furandicarboxyclic acid with 4(5)‐Methylimidazole as a high potential α‐glucosidase inhibitor: Synthesis, Crystal structure, Cytotoxicity study, and TD/DFT calculations

“…α‐Glucosidase, a critical enzyme for the digestion of carbohydrates, catalyzes the cleavage of absorbable monosaccharides, beginning from disaccharides and oligosaccharides . The functions of α‐glucosidase for mammals contain intestinal digestion of dietary carbohydrates, glycogen degradation, and glycoprotein folding and maturation . Besides, the inhibition of α‐glucosidases and related enzymes has a major role in the treatment of diabetes, human immunodeficiency virus (HIV/AIDS), cancer, and other degenerative diseases .…”

What Does the Future Hold for Yellow Fever Virus? (II)

“…The pyrazine carboxamide T-1106 has shown activity against YFV in the hamster model [334] and treatment with the T-705 (Favipiravir), an FDAapproved chemically-related compound, significantly improved disease parameters in YFV-infected hamsters when beginning administration up to 3 days post-infection [335]. Of note, T-705 in vitro activity against YFV was synergistically enhanced when combined with the ER α-glucosidase inhibitor IHVR-19029 [336]. Finally, a novel adenosine analogue, the pyridine carboxamide BCX4430, offered complete protection from mortality with significant improvement of other disease parameters in a hamster model, and remained effective even when treatment was initiated at the peak of viral replication (i.e.…”

Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro

“…In these studies, hepatocellular carcinoma cells with the knockout of α-glucosidases I or II supported a reduced level of ZIKV viral replication compared with wild-type cells (Ma et al, 2018). ER α-glucosidases I was more critical in reducing virus replication in comparison to ER α-glucosidase II (Ma et al, 2018). ZIKV viral replication was reduced in embryonic kidney cells when cells were treated with the iminosugar IVHR-19029 (Ma et al, 2018).…”

“…A promising avenue for effective anti-flaviviral therapeutics is a class of host-directed antivirals, namely iminosugars, with ER α-glucosidase inhibitor (ER-AGI) activity that are known to inhibit a range of enveloped RNA and DNA viruses in vitro by interrupting proper folding of viral proteins (Mehta et al, 1998;Chang et al, 2013a,b;Perry et al, 2013;Alonzi et al, 2017;Ma et al, 2018). Iminosugars are sugar mimetics in which cyclic oxygen is replaced with nitrogen.…”

“…Although iminosugars seem to be effective antivirals against many flaviviruses, only one recent report has examined the role of these compounds in ZIKV infection (Ma et al, 2018). In these studies, hepatocellular carcinoma cells with the knockout of α-glucosidases I or II supported a reduced level of ZIKV viral replication compared with wild-type cells (Ma et al, 2018). ER α-glucosidases I was more critical in reducing virus replication in comparison to ER α-glucosidase II (Ma et al, 2018).…”