Pathogen‐induced inflammation is attenuated by the iminosugar MON‐DNJ via modulation of the unfolded protein response

Abstract

Sepsis is a life‐threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non‐targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad‐spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen‐stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen‐induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis‐related inflammatory disorders associated with excess cytokine secretion.

Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects

“…This broad-spectrum activity has been extended recently to the coronaviruses including SARS-COV2 [ 29 , 45 ] Franco et al, submitted for publication]. UV-4 has also recently been shown to have beneficial effects on the host’s inflammatory response which is a hallmark of dengue, COVID-19, and other infectious diseases [ 31 ]. Dengue viruses cause pathophysiological responses that can respond to treatment.…”

“…Low potential for development of viral resistance has been confirmed with DENV and influenza [ 26 , 28 ]. Recent reports have identified potential of UV-4 and other iminosugars as therapeutics for coronaviruses [ 29 , 30 ] and inflammatory disorders associated with excess pathogen-induced cytokine secretion [ 31 ]. These findings supported evaluation of UV-4 in clinical trials.…”

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia

“…Synthetic glucosidase inhibitors (DNJ derivatives) have been reported to modulate Interferon gamma and TNFα receptor signalling in Dengue virus infection in primary human macrophages; this is possibly related to N -linked glycosylation changes [ 20 ]. In addition, it was proposed that these glucosidase-inhibiting iminosugars can control inflammation in viral, bacterial, and fungal sepsis [ 21 ]. The iminosugar idoBR1 is not a glucosidase inhibitor but, as a natural anti-inflammatory food iminosugar amino acid [ 5 ], it is of particular interest due to its possible dietary health benefits.…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…(1R)-1-C-Propyl-N-butyl-1-deoxynojirimycin Hydrocloride (19) General Procedure for the Synthesis of (1R)-N-(N′-Alkylthiocarbamoyl)-1-C-propyl-1-deoxynojirimycin Derivatives 21−26. To a solution of 13 (66 mg, 0.32 mmol) in pyridine (5.0 mL) were added Et 3 N (53 μL, 0.38 mmol) and the isothiocyanate reagent (0.35 mmol, 1.1 equiv).…”

“… 11 − 14 Disrupting the activity of carbohydrate-processing enzymes in pathogens can be further exploited in fighting infectious diseases: e.g., viral infections. 15 , 16 Innate immune response signaling routes, 17 , 18 cell proliferation and metastasis, 19 or age-related neurodegenerative disorders, e.g. Alzheimer and Parkinson diseases, 20 , 21 can also be targeted with iminosugars.…”