GW4 BioMed MRC DTP PhD studentship - Tightening the Noose on Parkinson’s disease: Harnessing Lasso Peptides as Inhibitors of alpha-Synuclein Toxicity

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 17 studentships for entry in October 2021.

+++ Note: Full funding may not be available for all applicants. Please see the Funding Notes below for more information +++

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found here: https://www.gw4biomed.ac.uk/.

SUPERVISORY TEAM:

Prof Jody Mason (lead), University of Bath, Department of Biology & Biochemistry https://researchportal.bath.ac.uk/en/persons/jody-mason
Dr Robert Williams, University of Bath, Department of Biology & Biochemistry
Prof Matthew Crump, University of Bristol, School of Chemistry

THE PROJECT:

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathies, including Parkinson’s disease (Meade et al, Mol Neurodegen 2019; Meade et al NPJ Parkinson’s disease 2020).

Building upon our expertise in this area, we will target αS using library-derived peptides via two highly novel elements: i) Grafting a peptide shown to bind αS and reverse toxicity (Cheruvara et al, 2015) into a short and highly structured lasso-peptide drug scaffold. Lassos are poorly exploited, yet harbour enormous potential to serve as a small rigid scaffold for drug design towards an entirely new drug class that is stable and specific, with the potential to transform PD treatment. ii) Use an intracellular peptide screening platform that targets αS upstream of misfolding. We will combine a novel assay we have developed, and our initial lead peptide, and graft it into the lasso loop for library design. We will scramble key residues required for effective binding, and use intracellular screening to search vast (>2M) libraries inside living cells. A key assay novelty is that only lassos which target monomeric αS and block toxicity via complete loss of aggregation will be identified.

Mason’s group is at the forefront of research in this area, where the student will create libraries, identify those that halt αS misfolding and toxicity and characterize peptide leads via a range of biophysical techniques (CD, ThT aggregation assays, Electron microscopy, crosslinking) to demonstrate efficacy. With Williams the student will move peptides into primary neuronal cells to demonstrate cell permeability, non-toxicity, and efficacy in synaptically active neurons. With Crump the student will utilize high-resolution NMR to identify key structures to identify the precise mechanism and residues by which αS and lasso interact, moving the project towards refinement by rational design. This interdisciplinary approach will generate high impact publications and potentially novel preclinical PD drug leads.

The proposal is collaborative, involving experts in peptide library screening and biochemistry (Mason), cellular neuroscience (Williams), and atomic resolution structural information (Crump) of the most effective molecules. The approach is novel and timely – protein-protein interactions (PPIs) are rapidly becoming validated as drug targets that are intractable to small molecules. This results from shallow binding grooves and broad interacting surfaces. Our recent work has generated serum stable cell-penetrant peptides that enter cells to inhibit both Activator Protein-1 transcriptional activity and cell proliferation (Baxter et al, ACS Chem Biol 2017). The lasso-approach to αS offers the potential for high target affinity and selectivity, using the same proteogenic residues that confer PPI specificity, while retaining stability and solubility akin to small molecule therapeutics, opening the door towards a generalized approach that could in future be applied to a wide number of other protein targets implicated in neurological disease.

APPLICATIONS:

Applicants must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form: https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl-2

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding form the DTP will be required to submit an application to study at Bath.

More information on the application process may be found here:
https://www.gw4biomed.ac.uk/doctoral-students/

APPLICATIONS CLOSE AT 17:00 ON 23 NOVEMBER 2020.