Ph.D. Studentship Targeting α-Synuclein Toxicity
Posted 25 Sep 2020
Department of Biology and Biochemisty, University of Bath
Bath, England, United Kingdom
In order to apply for this project, use 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/.
Building upon expertise in this area, the student will target αS using library-derived peptides via two highly novel elements: i) Grafting a peptide shown to bind αS and reverse toxicity into a short and highly structured peptide. These are poorly exploited, yet harbor enormous potential to serve as a small rigid scaffold for drug design toward 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 peptide 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 that target monomeric αS and block toxicity via complete loss of aggregation will be identified.
During the studentship 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 Dr. Robert Williams, the student will move peptides into primary neuronal cells to demonstrate cell permeability, nontoxicity, and efficacy in synaptically active neurons. With Professor Matthew Crump the student will utilize high-resolution NMR to identify key structures to identify the precise mechanism and residues by which αS and peptide interact, moving the project toward 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 (Professor Jody 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. The approach taken 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 toward a generalized approach that could in future be applied to a wide number of other protein targets implicated in neurological disease.
Prof Jody Mason (lead), University of Bath, Department of Biology & Biochemistry
Dr Robert Williams, University of Bath, Department of Biology & Biochemistry Prof Matthew Crump, University of Bristol, School of Chemistry
Funding Notes: U.K. students will be considered for a full 3.5-year studentship consisting of U.K. tuition fees, a research and training support grant of £2,000-£5,000 per annum and a stipend (£15,285 per annum for 2020/21, updated each year).
International applicants (including EU applicants) are also eligible to apply but will be required to pay the difference between the Home UKRI tuition fee . View website and the applicable University of Bath Overseas tuition fee rate website. Confirmation of ability to fund the tuition fee difference will be required.
APPLICATIONS CLOSE AT 5 P.M. ON 23 NOVEMBER 2020.
Applicants must have obtained, or be about to obtain, a First or Upper Second Class U.K. Honours degree, or the equivalent qualifications gained outside the U.K., in an area appropriate to the skills requirements of the project.