Dr Richard Doveston and Dr Andrew Hudson
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.
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.