Synthesis of Targeted Antiviral Nucleosides
Lead Research Organisation:
University of Oxford
Department Name: Oxford Chemistry
Abstract
This project tackles the unmet need for antiviral drugs targeted against SARS-Cov-2. We will construct a set of new carbocyclic C-nucleosides and test them as inhibitors of the virus which causes COVID-19. Antiviral therapies are urgently required to tackle this rapidly transmitted viral disease, which has resulted in over 3,000,000 infections and over 200,000 deaths globally (as of 28th April 2020). We have new technology which will enable the rapid construction of a library of carbocyclic Cnucleosides. Despite their promising biological activity as non-natural nucleoside mimics, this motif
is underexplored as an antiviral therapy on account of its difficult synthesis. The proposed approach enables the efficient synthesis of a diverse range of structures, resulting in a compound library primed for structure-activity relationship studies and the discovery of effective antiviral therapies. There is much similarity between the targets we propose and those in clinical trials, with the key difference being replacement of the oxygen atom in the sugar ring with a carbon atom. An important feature of our approach is the ability to produce a wide range of related compounds.
The synthesis of the library will be followed by biological testing in inhibition assays against the SARS-Cov-2 virus conducted by Ervin Fodor, with additional support from Chris Schofield on assay development and viral enzymology. Promising compounds will be subjected to structural studies,
in collaboration with Jonathan Grimes. All project partners are at the University of Oxford. Probing the nature of the interaction between the small molecules and the RNA virus replication machinery will increase our understanding of the mode of action of nucleoside therapeutics and
enable the design of small molecules with even greater activity.
is underexplored as an antiviral therapy on account of its difficult synthesis. The proposed approach enables the efficient synthesis of a diverse range of structures, resulting in a compound library primed for structure-activity relationship studies and the discovery of effective antiviral therapies. There is much similarity between the targets we propose and those in clinical trials, with the key difference being replacement of the oxygen atom in the sugar ring with a carbon atom. An important feature of our approach is the ability to produce a wide range of related compounds.
The synthesis of the library will be followed by biological testing in inhibition assays against the SARS-Cov-2 virus conducted by Ervin Fodor, with additional support from Chris Schofield on assay development and viral enzymology. Promising compounds will be subjected to structural studies,
in collaboration with Jonathan Grimes. All project partners are at the University of Oxford. Probing the nature of the interaction between the small molecules and the RNA virus replication machinery will increase our understanding of the mode of action of nucleoside therapeutics and
enable the design of small molecules with even greater activity.
Organisations
People |
ORCID iD |
| Stephen Fletcher (Principal Investigator) |
Publications
Mishra S
(2022)
Catalytic asymmetric synthesis of carbocyclic C-nucleosides
in Communications Chemistry
| Description | We have found some novel antiviral compounds. Some of our original target molecules had good levels of antiviral activity against SARS-COVID-19, but we also had some compounds tested that were synthetic intermediates, and these proved to be even more active. It was unexpected that these compounds would have antiviral activity |
| Exploitation Route | THe compounds that we have made and discovered had antiviral activity against SARS-COVID-19 may be active against other viruses, and these compounds and derivatives may serve as the basis of future small molecule medicines for developing antiviral treatments. We are currently preparing our first publication on this work, and preparing an initial patent filing. We are also trying to engage with more potential partners in this work, we do not currently have funding to work in the area, and we would like to get more help in testing and developing these compounds. Filing IP will allow us to be able to talk with potential partners to secure better preliminary results. We're quite keen to raise additional funding for this, but it has been tricky so far. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |