High dose iminosugar treatment: Investigation of a new antiviral mechanism of action (360G-Wellcome-203853_Z_17_A)

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Antiviral iminosugars inhibit endoplasmic reticulum (ER) a-glucosidases I and II (a-Glu), which induces misfolding of viral N-linked glycoproteins. ER a-GluII inhibition leads to the release of fewer infectious viruses in vitro and in vivo, and can protect mice from DENV- and influenza lethal challenge. We observed that inhibition of ER a-GluI can lead to similar life-saving effects in mice, even if enzyme inhibition is short lived and achieved by administration of a single dose of the drug. This is sufficient to create long-lived triglucosylated protein species that can prevent secretion of infectious virus for some time. We aim to understand this process. I first will establish cell lines that can be hosts for the viruses I am investigating in which to re-capitulate in vivo observations. I shall then proceed to identify which protein(s) are responsible for the long-lasting antiviral effect, why they are not degraded, and how they can exert an antiviral effect for longer than enzyme inhibition. This work may lead to new ways of treating viral diseases such as dengue, influenza and hepatitis B, prophylactically and/or therapeutically. Moreover, a field trip to Vietnam is planned to take advantage of clinical samples.

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Grant Details

Amount Awarded 0
Applicant Surname Brun
Approval Committee Internal Decision Panel
Award Date 2018-09-30T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title PhD Studentship (Basic)
Internal ID 203853/Z/17/A
Lead Applicant Miss Juliane Brun
Partnership Value 0
Planned Dates: End Date 2020-09-30T00:00:00+00:00
Planned Dates: Start Date 2017-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East