Award details

Development of novel broad-spectrum antiviral compounds for use in animals and humans

Reference	BB/W003295/1
Principal Investigator / Supervisor	Professor Kin-Chow Chang
Co-Investigators / Co-Supervisors	Dr Pavel Gershkovich, Professor Christopher Hayes
Institution	University of Nottingham
Department	School of Veterinary Medicine and Sci
Funding type	Research
Value (£)	611,514
Status	Current
Type	Research Grant
Start date	04/01/2022
End date	03/01/2024
Duration	24 months

Abstract

unavailable

Summary

The current pandemic highlights the need for effective antivirals to treat active infections, in conjunction with vaccines, to prevent infection. We recently made an important discovery of a highly effective broad-spectrum antiviral thapsigargin (TG), a specific inhibitor of the Ca2+ pump located on the cellular organelle endoplasmic reticulum (ER), that could be a game changer in the treatment of major human respiratory viruses: coronavirus (including SARS-CoV-2 that causes COVID-19), influenza virus and respiratory syncytial virus (RSV). TG's host-centred mechanism of action, as opposed to conventional direct acting antivirals, reduces the likelihood of drug resistant mutants emerging, a distinct advantage for treating highly mutable RNA viruses. Coronavirus, influenza virus, and RSV are also global pathogens of animals (including cattle, pigs and poultry). Antiviral development for livestock lags behind its human counterpart, despite its potential benefits of safeguarding animal health and productivity. Given that future pandemics are likely to be of animal origin, where animal to human (zoonotic) and reverse zoonotic (human to animal) spread take place, antivirals, such as TG and its derivatives, could play a key role in the treatment and control of important viral infections in both humans and animals. Thus, our goal in this proposal is to enhance the impact and commercial significance of TG through the generation of novel secondary derivatives with greater antiviral potency for animal and human use. We have established that TG is orally active as an antiviral, and that it is converted into a limited number of ester hydrolysis and side chain oxidation metabolites. We hypothesise that one or more of such TG metabolites are novel structures with enhanced antiviral activity. To this end, we propose to carry out detailed in vivo pharmacokinetics (PK) analyses of TG to fully determine its metabolites post-absorption, synthesise the main metabolites identified, and characterise the synthesised metabolites for antiviral activities to generate comprehensive cellular PK and antiviral data of the most promising TG derivative(s) for clinical development and commercial exploitation. TG and its derivatives represent a whole new generation of powerful host-centred antivirals (as opposed to conventional antiviral drugs that directly target viruses) that could be adopted in a holistic "One Health" approach to control human and animal viruses. The outcomes of this project could have far-reaching impact on a global scale in the treatment and control of RNA viral infections of human and animal importance.

Committee	Not funded via Committee
Research Topics	Animal Health, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Follow-On Fund Super (SuperFOF) [2012-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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