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Assembling a toolbox to study protein molecular glue kinetics.

  • Full or part time
  • Application Deadline
    Thursday, November 21, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

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.

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.
For full application information and the link to the online application please go to:
https://le.ac.uk/study/research-degrees/funded-opportunities/cse-chemistry-doverston-2020

Project / Funding Enquiries:
Application enquiries to
Closing date for applications 21st November 2019

Funding Notes

This project is eligible for a fully funded 3.5 year College of Science and Engineering studentship which includes:
• A full UK/EU fee waiver for 3.5 years - International applicants will need to provide evidence they can fund the difference between the UK/EU fee and International fee
• An annual tax free stipend of £15,009 (2019/20)
• Research Training Support Grant (RTSG)

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.

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