Presentation Transcript

1. Drugging the Undruggable…Protein-Protein Interactions

   Professor Robin Leatherbarrow Head of Biological Chemistry Department of Chemistry
2. What is a “typical” Drug? Modulates a specific biological process Enzyme inhibitor Reversible competitive inhibitor e.g. Viagra Irreversible enzyme inhibitor e.g. Penicillin, aspirin Small molecular weight compound Obeys Lipinski “rule of 5” Less than 500 molecular weight etc Orally available
3. The ‘Druggable’: Inhibiting Enzyme-Substrate Interactions Enzyme with a defined substrate-binding site P P Enzyme Substrate binds and is converted to product(s) I Inhibitor blocks substrate binding S S S
4. The ‘Undruggable?’: Inhibiting Protein-Protein Interactions Protein responsible for biological effect Protein 1 Effect modulated by protein-protein interaction I Protein 2 Inhibitor regulates effect by blocking protein-protein interaction Biological Effect
5. What proportion of drug targets are druggable? Human genome: 30,000 drug targets Disease-related targets:  10% Figures from Hopkins and Groom (2002) Nature Rev Drug Disc 1, 727
6. Why Target Protein-Protein Interactions? Account for the majority of biological control points Are implicated in all areas of medicine Wide ranging impact Many therapeutic areas …BUT ARE DIFFICULT TO TARGET
7. Problems… Protein 1 Protein 2 S Enzyme
8. Examples to date There are a few examples of successful drug leads that are targeted at Protein-Protein interfaces However, there are currently NO marketed drugs that work this way… Review: Wells & McClendon (2007) Nature450, 1001
9. 1. Bcl-XL binders B-cell lymphoma (Bcl) 2 family proteins are important regulators of apoptotic cell death and form homodimers with other family members Bcl-XL (grey) bound to partner protein via alpha helical region Bound small molecule inhibitor of this interaction
10. 2. IL-2 binders Interleukin-2 is a cytokine that has a key role in activation of T cells and in the rejection of tissue grafts, by binding to IL-2 receptor IL-2 (grey) bound to partner protein Bound small molecule inhibitor of this interaction
11. 3. HPV E2 binders Human papilloma virus (HPV) causes warts and some cervical cancers. The interaction between HPV transcription factor E2 and helicase E1 is vital for the viral life cycle HPC E2 (grey) bound to EPV E1 Bound small molecule inhibitor of this interaction
12. Issues Where do we start? Fragment screening? Peptidomimetic approaches? Allosteric modulation? How do we assay? Throughput / sensitivity? How do we optimise leads? Starting points not “drug-like”?
13. Trypsin – Trypsin Inhibitor interactions Trypsin Inhibitor Protein (BBI) Trypsin Interacting region
14. Constrained Peptides as Functional Motifs Protease Synthetic interacting motif Ki= 9 nM Trypsin Inhibitor Protein (BBI)
15. Assay: Droplet-based Microfluidics Discrete liquid droplets are encapsulated by a carrier fluid Droplets: are isolated and form the dispersed phase in which reactions may occur can be dosed with varying amounts of input reagents can be generated at kHz frequencies Andrew de Mello, Imperial College
16. Measuring Protein-Protein Interactions in Microdroplets Angiogenin – anti-Angiogenin KD = 6.4 nM Monpichar Srisa-Art, Dong-Ku Kang, Jongin Hong, Hyun Park, Robin J. Leatherbarrow, Joshua B. Edel, Soo-Ik Chang, and Andrew J. deMello; ChemBioChem2009
17. Conclusions Protein-protein interactions are potentially extremely useful drug targets They are far more difficult than “traditional” drug targets They offer new therapeutic possibilities that should become exploited in coming years