| EPSRC Reference: |
EP/S027246/1 |
| Title: |
Hijacking prenyl and geranyl transferases - A route to carry out click modifications and to enhance cellular permeability of peptides |
| Principal Investigator: |
Houssen, Dr W |
| Other Investigators: |
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| Project Partners: |
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| Department: |
Chemistry |
| Organisation: |
University of Aberdeen |
| Scheme: |
EPSRC Fellowship |
| Starts: |
01 August 2019 |
Ends: |
31 July 2024 |
Value (£): |
1,032,570
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| EPSRC Research Topic Classifications: |
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| EPSRC Industrial Sector Classifications: |
| No relevance to Underpinning Sectors |
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| Panel History: |
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Summary on Grant Application Form |
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Recent advances in biological research have allowed a better understanding of the causation of many diseases and identified new targets for therapy. An ideal drug should bind to a specific cellular target and have no affinity to others. One of the recently identified challenging targets for drug discovery is the protein-protein interactions that have been proved to be involved in many difficult-to-treat diseases e.g. immune disorders and cancer. These interactions are taking place along the extended surface of large proteins and thus are very challenging for small molecule drugs. Biological drugs e.g. antibodies are large molecules and can disrupt protein-protein interactions but cannot be administered orally and are very expensive. Macrocyclic peptides are an emerging class of drug candidates that have the ability to disrupt protein-protein interactions e.g. the immune-suppressant, cyclosporin that made transplant surgery possible. They are smaller in size and are very much cheaper than biologics. In contrast to their linear "non-cyclic" counterparts, they are more stable against enzymes and are semi-rigid to fit better with their targets much like a key fits into a lock. A limitation that hampers the development of many of these compounds is their low ability to cross cellular membranes and to reach intracellular targets. Several modified cyclic peptides are commonly found in medicinal natural products. These compounds were evolved via natural selection which is presumably driven by their pharmacological potency against specific molecular targets as well as their ability to reach these targets that is, by crossing one or more biological membranes. In nature, several modifications are introduced to cyclic peptides to enhance membrane permeability. These modifications aim to reduce the hydrophilic (polar) surface of the molecule by shielding with hydrophobic side chains thus the compound can easily diffuse through the hydrophobic (mainly lipid) cellular membranes. Ideally these modifications should be applied to specific sites to avoid a large reduction in water solubility or the change of three dimensional shape of the molecule with subsequent decrease in its ability to bind to its target. Recent research revealed how a large group of these modified cyclic peptides is made inside their hosts. In this project, I will identify and recruit new modifying biosynthetic enzymes that will add hydrophobic chemical groups such as prenyl and geranyl groups at specific sites in cyclic peptides. Making these modifications using chemical methods is very challenging, not eco-friendly and in most cases entails total re-synthesis which is time consuming. I will determine the structure and biochemical features of these enzymes to identify the key residues that underlie their activity and specificity. I will use these insights to engineer and generate enzyme variants with different residue specificity and ability to introduce other chemical groups. I will use chemical synthesis and the engineered enzymes to generate modified derivatives of bespoke bioactive cyclic peptides and test the effect of different modifications on membrane permeability and the three dimensional shape of the molecule that underlies target affinity. These data will help to generate a computational model to predict membrane permeability of bioactive cyclic peptides that will be invaluable for development of peptides into drugs.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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| Project URL: |
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| Further Information: |
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| Organisation Website: |
http://www.abdn.ac.uk |