| EPSRC Reference: |
EP/Z533002/1 |
| Title: |
Creating an intracellular screening platform for cyclic peptide drug discovery |
| Principal Investigator: |
Mason, Professor JM |
| Other Investigators: |
|
| Researcher Co-Investigators: |
|
| Project Partners: |
|
| Department: |
Life Sciences |
| Organisation: |
University of Bath |
| Scheme: |
Standard Research TFS |
| Starts: |
01 August 2024 |
Ends: |
30 September 2025 |
Value (£): |
153,660
|
| EPSRC Research Topic Classifications: |
| Drug Formulation & Delivery |
Protein chemistry |
|
| EPSRC Industrial Sector Classifications: |
|
| Related Grants: |
|
| Panel History: |
|
|
Summary on Grant Application Form |
3. Intracellular Macrocyclization of Peptides by AEP catalysis with TBS (IMPACT) - Couple our improved OaAEP1 with an in-cell peptide screening platform known as Transcription Block Survival (TBS - https://doi.org:10.1021/jacsau.2c00105), to facilitate a tag-free genetically encoded peptide library screen that identifies cyclic peptides that functionally antagonise a highly important yet currently undruggable target space - transcription factors. This will translate OaAEP1 from a biological curiosity to a drug discovery tool that facilitates production of head-to-tail constrained peptides. For proof-of-concept, we will deploy cJun as the target protein, and initially couple with a small cyclic peptide (CP1 - https://doi.org /10.1038/nbt1412), previously reported to antagonise cJun activity with low potency (micromolar IC50). CP1, and later other cyclotides, will serve as design templates to generate 64-million-member cyclic peptide libraries to be screened against cJun using IMPACT.
Deliverable: Proof-of-concept for IMPACT; a transformative healthcare technology platform, enabling high throughput intracellular cyclic peptide screening. Identifying peptides in the cyclic form, based on functional antagonism, within the challenging cellular environment ensures only those with real therapeutic promise are selected and improves the rate of success during drug discovery.lls. This will be achieved by partially scrambling the amino acid sequence of OaAEP1 at solvent exposed positions to generate a 589,824-member library which will be screened for activity using split dihydrofolate reductase (mDHFR). Only ligation of mDHFR fragments will enable reconstitution of activity resulting in cell growth, with subsequent competition selection enriching the most soluble and active OaAEP1 library members.
Deliverable: An engineered enzyme optimised for intracellular catalysis. The selection assay also allows rapid engineering of the enzyme by directed evolution to further modify attributes such as substrate specificity.
|
|
Key Findings |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
|
Potential use in non-academic contexts |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
|
Impacts |
|
| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
|
| Date Materialised |
|
|
|
|
Sectors submitted by the Researcher |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
| Project URL: |
|
| Further Information: |
|
| Organisation Website: |
http://www.bath.ac.uk |