Assembling a toolbox to study protein molecular glue kinetics.

Qualification: PhD

Department: School of Chemistry

Application deadline: 21st November 2019

Start date: 28th September 2020

Overview

Supervisors

Dr Richard Doveston and Dr Andrew Hudson

Project Description:

Interactions between proteins form a communication network that is an essential feature of life. In many human diseases, especially cancer, one or more these interactions become dysregulated. Therefore targeting protein-protein interactions (PPI) with drug molecules is an attractive therapeutic strategy. In recent years much progress has been made toward developing drugs that inhibit PPIs associated with a disease. The opposite strategy of using a drug molecule as a ‘glue’ to stabilise PPIs critical to the fight against disease has however been under-exploited. This is despite enormous potential, with an estimated 300,000 PPIs to target!

This interdisciplinary project will complement existing research activity in chemical biology (Doveston group) and single-molecule biophysics (Hudson group) within the Leicester Institute of Structural and Chemical Biology (LISCB). It will develop a toolkit for measuring the kinetic aspects of PPI stabilisation. PPI stabilisation is a complex phenomenon often involving weak and transient interactions between three molecules (two proteins and the ‘glue’). Existing analytical approaches rely on structural or thermodynamic techniques that often cannot accurately measure, or even detect, weak interactions. This has serious implications for drug discovery and development because new ‘hits’ might be overlooked and key data needed to guide optimisation is not available.  Being able to determine the kinetic parameters of PPI stabilisation would directly resolve this problem, but the commonly available techniques require one of the molecules to be immobilised on an artificial surface. This limits their application and likely compromises physiological relevance. The project will therefore develop robust and broadly applicable experiments carried out in solution and close to physiological conditions. It is envisaged that the molecular and technological outputs of the project will have a big impact on drug discovery.

Interactions involving the 14-3-3 family of adapter protein will be studied in a developmental case study. 14-3-3 proteins play numerous roles in the cell and have many binding partners that are implicated in disease. It is the perfect test-bed system because: i) an accessible natural product stabiliser has already been well described; ii) a vast amount of structural information is at hand and; iii) the binding motifs of partner proteins can be mimicked using versatile synthetic peptides. 

References: 

1. Stabilization of protein-protein interactions in drug discovery. S. A. Andrei, E. Sijbesma, R. G. Doveston et al., Exp. Op. Drug Discov. 2017, 925-940.

2. Small Molecule Modulators of 14-3-3 Protein-Protein Interactions, L. M. Stevers, E. Sijbesma, R. G. Doveston et al., J. Med. Chem. 2018, 61, 3755-3778.

3. Modulators of Protein-Protein Interactions, L-G. Milroy, C. Ottmann et al., Chem. Rev. 2014, 114, 4695-4748.

4. Watching proteins fold one molecule at a time, E. Rhoades, E. Gussakovsky and G. Haran, Proc. Nat. Acad. Sci. USA 2003, 100, 3197-3202.

Funding

Funding

UK/EU applicants

This research project is eligible for a fully funded College of Science and Engineering studentship which includes:

A full UK/EU fee waiver for 3.5 years

An annual tax free stipend (For 2019/20 this is currently £15,009)

Research Training Support Grant (RTSG)

International Applicants

This project is eligible for a partially funded College of Science and Engineering studentship which includes:

A full UK/EU fee waiver for 3.5 years (applicants will need to provide evidence they can fund the difference between the UK/EU fee and International fee for the duration of their studies)

An annual tax free stipend of £15,009 (2019/20)

Research Training Support Grant (RTSG)


Entry requirements

Entry requirements

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject or overseas equivalent.
The University of Leicester English language requirements apply where applicable.

Informal enquiries

Informal enquiries

Project / Funding Enquiries: csepgr@le.ac.uk

Application enquiries to pgradmissions@le.ac.uk


How to apply

How to apply

Please use the Apply button at the bottom of the page. Select September 2020 entry.

Application Notes

We recommend you apply as early as possible so that any missing information can be obtained before the deadline.

In the funding section of the form state CSE2020 Doveston Studentship

In the research proposal section include the name of the supervisors and project title.  If you are applying for more than one project within Chemistry include details of each project.

In the personal statement section upload your completed CSE Studentship Form. If you are applying for more than one Chemistry project complete a form for each project and email the additional forms to csepgr@le.ac.uk together with your application ID number. If you are applying for projects in other subject areas please submit separate PhD applications online.

Upload a copy of your CV, copies of your degree certificates and transcripts if awarded and evidence of English language proficiency if applicable and available.

If you already have reference letters please upload these. If not enter the contact details of your referees in the reference section. Please ask your referees if they can submit their references as quickly as possible, ideally within two weeks of receipt of our reference request.

Application timetable

21st November Deadline for applications and all supporting documents 
9th December Interview invitations to be sent out by email
w/c 13th January 2020  Interviews
21st January 2020 Informal offers to be made
31st January 2020 Deadline for acceptable of informal offers 

The PGR Admissions Office will notify unsuccessful applicants once a decision has been made.

Eligibility

Eligibility

UK/EU applicants

International applicants who can demonstrate that they can pay the difference between UK/EU and International fees.