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  7. Perturbation of Protein-Protein Interactions (PoPPI)

Research project

Perturbation of Protein-Protein Interactions (PoPPI)

  • Start date: 1 February 2016
  • End date: 31 January 2022
  • Funder: EPSRC
  • Value: £2,751,527
  • Partners and collaborators: University of Bristol, Newcastle University, Domainex, AstraZeneca
  • Primary investigator: 00917043
  • Co-investigators: Professor Adam Nelson
  • Co-investigators (additional Faculties): Professor Thomas A Edwards 
  • External co-investigators: Professor Dek Woolfson (University of Bristol), Dr Richard Sessions (University of Bristol)
  • Postgraduate students: Kristina Hetherington, Suzanne Renwick

Poppi

Introduction

PoPPI is a £3.4 million five-year collaborative programme, funded by the Engineering and Physical Sciences Research Council (EPSRC), between the ​University of Leeds University of Bristol Northern Institute for Cancer Research (Newcastle University) AstraZeneca Domainex.

The programme focuses on the development of computational and chemical tools to classify protein-protein interactions (PPI) and use the resultant insight to synthesize molecules, which act as selective inhibitors and, which can be used as chemical probes. Understanding and modulating the PPIs will increase the knowledge of the underlying mechanisms of diseases, such as cancer and the neurodegenerative diseases, e.g. Alzheimer’s, Huntingdon’s and Parkinson’s.

Research focus

Protein-Protein Interactions (PPI) are important as they are involved in all cellular processes, both healthy and disease related. In layman’s terms, the interaction in PPIs can be considered as a hand gripping a ball, where one protein grips the other. PPI’s are important in maintaining the healthy status of the living cells and the human body, but on occasions these can be disrupted or malfunction, leading to the development and progression of diseases, such as cancer or a neurodegeneration (e.g. Alzheimer’s).

One potential route for the treatment of diseases associated with malfunctioning PPIs is to develop drug-like small molecules to inhibit the interactions between the two proteins. Until recently, PPIs were considered too challenging to inhibit using small-molecules, but recently their potential use has been demonstrated by the Nutlin series (Roche) and Navitoclax (Abbott). The issue lies with identifying which PPIs could be targeted by the small molecule inhibitor, and be used for drug discovery.

This programme seeks to address these challenges. The programme aims to create the tools to make this kind of drug discovery easier by analysing and categorising the important features of protein-protein interactions. This will provide the basis for discovering many new drugs for the treatment of disease.

Conferences 

Protein-Protein Interactions 2019 - Organised jointly by SCI’s Fine Chemicals Group and RSC’s Biological and Medicinal Chemistry Sector in association with PPI-Net 4/5 April 2019.
Joint PPI-net/ PoPPI Conference ‘Protein-protein interactions: the next frontier’ hosted online 15th Sept 2020. 

Schools/Institutes involved include: School of Chemistry, Chemical Biology and Medicinal Chemistry, Faculty of Biological Sciences, School of Molecular and Cellular Biology, The Astbury Centre for Structural Molecular Biology

Publications and outputs

Wang, H., Dawber, R., Zhang, P., Walko, M., Wilson, A.J. & Wang, X. (2021) Peptide-Based Inhibitors of Protein-Protein Interactions: Biophysical, Structural and Cellular Consequences of Introducing a Constraint, Chem. Sci., in press.

Ueda, T., Tamura, T., Kawano, M., Shiono, K., Hobor, F., Wilson, A.J. & Hamachi, I. (2021) Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N-Acyl-N-alkyl Sulfonamide Warhead J. Am. Chem. Soc. 143, 12, 4766–4774.

Celis, S., Hobor, F.,  James, T., Bartlett, G.J., Ibarra, A.A., Shoemark, D.K., Hegedus, Z., Hetherington, K., Woolfson, D.N., Sessions, R.B., Edwards, T.A. , Andrews, D.M.,  Nelson, A. & Wilson, A.J. (2021) Query-Guided Protein-Protein Interaction Inhibitor Discovery, Chem. Sci. 10.1039/d1sc00023c.

Hegedüs, Z., Hobor, F., Shoemark,  D.K., Lian, L.-Y., Trinh, C., Sessions, R.B., Edwards, T.A. & Wilson, A.J. (2021) Identification of β-Strand Mediated Protein-Protein Interaction Inhibitors Using Ligand-Directed Fragment Ligation, Chem. Sci., 12, 6, 2286-2293.

Cawood, E.E., Karamanos, T.K., Wilson, A.J. & Radford, S.E. (2021) Visualizing and trapping transient oligomers in amyloid assembly pathways, Biophys. Chem., 268, 106505.

Cawood, E.E., Guthertz, N., Ebo, J., Karamanos, T., Radford, S.E. & Wilson, A.J. (2020) Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules, J. Am. Chem. Soc., 142, 49, 20845–20854.

Miles, J., Hobor, F., Trinh, C., Taylor, J., Tiede, C., Rowell, C., Jackson, B., Nadat, F., Ramsahye, P., Kyle, H., Wicky, B., Clarke, J., Tomlinson, D., Wilson, A.J., Edwards, T.A. (2020) Selective Affimers Recognize the BCL‐2 Family Proteins BCL‐xL and MCL‐1 through Non‐Canonical Structural Motifs, ChemBioChem, 22, 1, 232-240.

Wolter, M., de Vink, P., Neves, J.F., Srdanovic, S., Higuchi, Y.,  Kato, N., Wilson, A.J., Landrieu, I., Brunsveld, L., & Ottmann, C. (2020) Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 interaction with Semi-Synthetic Natural Products, J. Am. Chem. Soc., 142, 27, 11772–11783.

Green, A., Hobor, F., Tinworth, C., Warriner, S., Wilson, A.J., & Nelson, A. (2020) Activity‐directed synthesis of inhibitors of the p53/hDM2 protein‐protein interaction, Chem.Eur., 26, 47, 10682-10689.

Hetherington, K., Hegedus, Z., Edwards, T.A., Sessions, R.B., Nelson, A., Wilson, A.J. (2020) Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency, Chem. Eur. J., 26, 34, 7638-7646.

Lindsey-Crosthwait, A., Rodriguez-Lema, D., Walko, M., Pask, C. and Wilson, A.J. (2020) Structural optimization of reversible dibromomaleimide peptide stapling, Peptide Science, 113, 1, e24157.

Wood, C.W., Ibarra, A.A., Bartlett, G.J., Wilson, A.J., Woolfson, D.N., Sessions, R.B. (2020) BAlaS: fast, interactive and accessible computational alanine-scanning using BudeAlaScan, Bioinformatics, 36, 9, 2917–2919.

Ibarra, A.,  Bartlett, G.J., Hegedus, Z., Dutt, S., Hobor, F.,  Horner, K., Hetherington, K., Spence, K., Nelson, A., Edwards, T.A., Woolfson, D.N., Sessions, R., Wilson, A.J. (2019) Predicting and Experimentally Validating Hot-Spot Residues at Protein-Protein Interfaces, ACS Chem. Biol., 14, 10, 2252–2263.

Beard, H.A., Hauser, J.R., Walko, M., George, R.M., Wilson, A.J. & Bon, R.S. (2019) Photocatalytic Proximity Labelling of MCL-1 by a BH3 Ligand, Commun. Chem., 2, 133, doi:10.1038/s42004-019-0235-z

Bunce, S.J., Wang, Y., Stewart, K.L., Ashcroft, A.E., Radford, S.E., Hall, C.K., Wilson, A.J (2019) Molecular Insights into the surface catalyzed secondary nucleation of Amyloid-β40 (Aβ40) by the peptide fragment Aβ16-22, Sci. Adv., 5, 6, eaav8216.

Wang, Y., Bunce, S., Radford, S.E., Wilson, A.J., Auer, S., Hall, C.K. (2019) Thermodynamic Phase Diagram of Amyloid-β (16-22) Peptide, Proc. Natl. Acad. Sci. USA, 116, 6, 2091-2096.

Hegedus, Z., Grison, C. M.,  Miles, J.A., Rodriguez-Marin, S., Warriner, S.L., Webb, M.E., Wilson, A.J. (2019) A Catalytic Protein–Proteomimetic Complex: Using Aromatic Oligoamide Foldamers as Activators of RNase S, Chem. Sci., 10, 3956-3962.

Bakail, M., Rodriguez-Marin, S., Hegedüs, Z., Perrin, M.E., Ochsenbein, F., Wilson, A.J. (2019) Recognition of ASF1 Using Hydrocarbon Constrained Peptides, ChemBioChem, 20, 7, 891-895.

Dos Santos Rodrigues, F.H.,  Firczuk, H., Breeze, A.L., Cameron, A.D., Walko, M.,  Wilson, A.J.,  Zanchin, N.I.T., McCarthy, J.E.G. (2019) The Leishmania PABP1–eIF4E4 interface: a novel 5′–3′ interaction architecture for trans-spliced mRNAs. Nucleic Acids Res., 47, 3, 1493-1504.

Horne, M., Walko, A. N., Calabrese, M. A., Levenstein, D. J., Brockwell, N., Kapur, A. J. Wilson, Radford, S.E. (2018) Rapid Mapping of Protein Interactions Using Tag-Transfer Photocrosslinkers. Angew. Chemie. Int. Ed., 57, 51, 16688–16692.

Fletcher, J.M., Horner, K.A., Bartlett, G.J., Rhys, G.G., Wilson, A.J., Woolfson, D.N. (2018) De novo coiled-coil peptides as scaffolds for disrupting protein–protein interactions. Chem. Sci., 9, 7656-7665.

Hewitt, S.H. & Wilson, A.J. (2018) Generation of Dynamic Combinatorial Libraries Using Hydrazone Functionalized Surface Mimetics. Eur. J. Org. Chem, 1872-1879.

Hewitt, S.H. & Wilson, A.J. (2017) Protein Sensing and Discrimination Using High Functionalised Ruthenium (II) tris(Bipyridyl) Protein Surface Mimetics in an Array Format. Chem. Commun. 53, 12278-12281.

Project website

https://poppi.website/