Iminosugars: Promising therapeutics for influenza infection

Tyrrell, Beatrice E.; Sayce, Andrew C.; Warfield, Kelly L.; Miller, J. F. A. P.; Zitzmann, Nicole

doi:10.1080/1040841x.2016.1242868

Cited by 47 publications

(32 citation statements)

References 158 publications

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“… 29 Current basic knowledge of common anti-influenza neuraminidase inhibitors is summarized in Table 1 and discussed in more detail in recent publications. 30 …”

Section: Introductionmentioning

confidence: 99%

Inhibition of sialidase activity as a therapeutic approach

Glanz

Myasoedova

Grechko

et al. 2018

DDDT

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The demand for novel anti-influenza drugs persists, which is highlighted by the recent pandemics of influenza affecting thousands of people across the globe. One of the approaches to block the virus spreading is inhibiting viral sialidase (neuraminidase). This enzyme cleaves the sialic acid link between the newly formed virions and the host cell surface liberating the virions from the cell and maintaining the cycle of infection. Viral neuraminidases appear therefore as attractive therapeutic targets for preventing further spread of influenza infection. Compared to ion channel blockers that were the first approved anti-influenza drugs, neuraminidase inhibitors are well tolerated and target both influenza A and B viruses. Moreover, neuraminidase/sialidase inhibitors may be useful for managing some other human pathologies, such as cancer. In this review, we discuss the available knowledge on neuraminidase or sialidase inhibitors, their design, clinical application, and the current challenges.

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“… 29 Current basic knowledge of common anti-influenza neuraminidase inhibitors is summarized in Table 1 and discussed in more detail in recent publications. 30 …”

Section: Introductionmentioning

confidence: 99%

Inhibition of sialidase activity as a therapeutic approach

Glanz

Myasoedova

Grechko

et al. 2018

DDDT

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“…The best-known class of such ERQC modulators are iminosugars, glucose analogues that have the potential to act as broad-spectrum antivirals. Iminosugars target the host’s ERQC and negatively affect the folding of a number of enveloped viral glycoproteins [ 7 , 8 , 9 , 10 , 11 ]. The cross reactivity of iminosugars with intestinal glucosidases and enzymes of the glycosphingolipid pathway [ 12 ] highlights the need to expand the search for ERQC modulators to different scaffolds.…”

Section: Introductionmentioning

confidence: 99%

In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators

Marti

Lia

Reca

et al. 2018

IJMS

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Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.

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“…Glycosylation-associated drugs are beginning to make an impact in human health, and there is reason to anticipate success in combating pathogens with their distinctive glycan synthetic pathways (27)(28)(29)(30). Unique glycoconjugates are prime candidates for vaccine development and as markers for diagnostic monitoring.…”

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confidence: 99%

CRISPR/Cas9 and glycomics tools for Toxoplasma glycobiology

Gas-Pascual

Ichikawa

Sheikh

et al. 2019

Journal of Biological Chemistry

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Infection with the protozoan parasite Toxoplasma gondii is a major health risk owing to birth defects, its chronic nature, ability to reactivate to cause blindness and encephalitis, and high prevalence in human populations. Unlike most eukaryotes, Toxoplasma propagates in intracellular parasitophorous vacuoles, but like nearly all other eukaryotes, Toxoplasma glycosylates many cellular proteins and lipids and assembles polysaccharides. Toxoplasma glycans resemble those of other eukaryotes, but species-specific variations have prohibited deeper investigations into their roles in parasite biology and virulence. The Toxoplasma genome encodes a suite of likely glycogenes expected to assemble N-glycans, O-glycans, a C-glycan, GPI-anchors, and polysaccharides, along with their precursors and membrane transporters. To investigate the roles of specific glycans in Toxoplasma, here we coupled genetic and glycomics approaches to map the connections between 67 glycogenes, their enzyme products, the glycans to which they contribute, and cellular functions. We applied a double-CRISPR/Cas9 strategy, in which two guide RNAs promote replacement of a candidate gene with a resistance gene; adapted MS-based glycomics workflows to test for effects on glycan formation; and infected fibroblast monolayers to assess cellular effects. By editing 17 glycogenes, we discovered novel Glc 0-2-Man 6-GlcNAc 2-type N-glycans, a novel HexNAc-GalNAc-mucin-type O-glycan, and Tn-antigen; identified the glycosyltransferases for assembling novel nuclear O-Fuc-type and cell surface Glc-Fuc-type O-glycans; and showed that they are important for in vitro growth. The guide sequences, editing constructs, and mutant strains are freely available to researchers to investigate the roles of glycans in their favorite biological processes. Toxoplasma gondii is a worldwide, obligate intracellular apicomplexan parasite that can infect most nucleated cells of warm-blooded animals (1), with up to 80% of some human populations being seropositive (2). Toxoplasmosis, the disease caused by Toxoplasma, is associated with encephalitis and blindness in individuals whose parasites are reactivated, as can occur in AIDS and other immunosuppressed patients (3). In utero infections can cause mental retardation, blindness, and death (4). Toxoplasma is transmitted by digesting parasites from feline feces (as oocysts) or undercooked meat (as tissue cysts). Once in the host, parasites convert to the tachyzoite form that disseminates to peripheral tissues (e.g. brain, retina, and muscle). The resulting immune response and/or drugs can control tachyzoite replication, but the parasite survives by encysting into slowly growing bradyzoites. Sporadically, burst of cysts allows the parasites to convert to tachyzoites, whose unchecked growth results in cell and tissue damage (5, 6). Currently, no Toxoplasma vaccine exists, anti-toxoplasmosis drugs have severe side effects, and resistance is developing to these drugs (7-11). As individuals remain infected for life, new anti-Toxoplasma drugs a...

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Iminosugars: Promising therapeutics for influenza infection

Cited by 47 publications

References 158 publications

Inhibition of sialidase activity as a therapeutic approach

Inhibition of sialidase activity as a therapeutic approach

In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators

CRISPR/Cas9 and glycomics tools for Toxoplasma glycobiology

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