Antiviral and immunomodulatory activities of iminosugars: candidate therapeutics for arbovirus infections

Thesis

The antiviral efficacy of iminosugars with glucose-stereochemistry has been demonstrated against a broad range of enveloped viruses possessing N-glycoproteins. This antiviral activity is primarily understood to be mediated by competitive inhibition of endoplasmic reticulum (ER) α-glucosidases, leading to a reduction in functional viral glycoprotein folding and infectious virion production.

Dengue virus (DENV) is one such virus for which iminosugar efficacy has previously been established. Here, the antiviral efficacy of N-8’-2’’-tetrahydrofuranyl-octyl-deoxynojirimycin (2THO-DNJ) is evaluated against DENV infection of primary human monocyte-derived macrophages (MDMΦs). The potential for iminosugars to impact stages of the DENV infection cycle in addition to virion secretion is considered, and DNJ-derivative iminosugars are demonstrated to inhibit DENV replication in primary human immune cells for the first time. Alongside DENV, iminosugar efficacy against Zika virus (ZIKV) is investigated, finding important differences in the iminosugar susceptibility and ER α-glucosidase dependence of the two viruses.

Moving away from flaviviruses, the potential for iminosugars to be employed against the emerging Crimean-Congo haemorrhagic fever virus is considered, through use of the little-characterised ‘surrogate’ Hazara virus (HAZV). Despite possession of N-glycoproteins, a lack of iminosugar antiviral activity is observed in HAZV-infected SW13 cells.

Common to viral haemorrhagic fevers and certain other disease states is a strong pro-inflammatory, pathological immune response. Immunomodulatory activity of iminosugars has previously been reported, but with a limited range of stimuli used. Here, the impact of iminosugars on cytokine responses to both viral infection and stimulation of MDMΦs with a spectrum of pattern-associated molecular patterns (PAMPs) is investigated, with secretion of biologically functional TNF-α the major read-out. The suppressive effects of DNJ-derivative iminosugars on TNF-α secretion are broadly conserved across stimuli, supporting previous findings that iminosugar immunomodulatory activity is not dependent on viral replication or restricted to PAMPs of a viral origin. In contrast, the galactostereochemistry iminosugar N-nonyl-deoxygalactonojirimycin had more selective effects on cytokine production than the corresponding DNJ-derivative. Preliminary mechanistic investigations considering potential effects of iminosugars on TLR signalling pathways are conducted.

Overall, this thesis explores exciting new features and nuances of iminosugar activities relevant for treating viral infections and combatting a wider range of inflammatory conditions.

Authors: Tyrrell, B

• DOI: 10.5287/ora-b72qm1xpx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford