Professor Robin Leatherbarrow Head of Biological Chemistry Department of Chemistry

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

S S I I P P S S P P S S Enzyme Enzyme with a defined substrate- binding site Substrate binds and is converted to product(s) Inhibitor blocks substrate binding

Protein 1 Protein responsible for biological effect Effect modulated by protein-protein interaction Inhibitor regulates effect by blocking protein-protein interaction Protein 2 I

Human genome:  30,000 drug targets Disease-related targets:  10% Figures from Hopkins and Groom (2002) Nature Rev Drug Disc 1, 727

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

Typical Enzyme-Substrate InteractionTypical Protein-Protein Interaction Well-defined binding pocketRelatively flat surface Relatively small contact area ( Å 2 ) Relatively large contact area ( Å 2 ) Intrinsic interaction is relatively weak, so easy to block Intrinsic interaction is relatively strong… Screening involves looking for compounds that affect enzyme activity—assay is easy No enzyme assay for easy screening Substrate structure gives “clues” towards inhibitor design No such information available Inhibitors the size of the substrate are still likely to be small (Rule of 5 compliant) Inhibitors of comparable size to the interacting surface will be too large There are MANY examples of successful drugs that target enzymes There are VERY FEW examples of any drugs that target Protein-Protein interactions Protein 1 Protein 2 S S Enzyme

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) Nature 450, 1001

B-cell lymphoma (Bcl) 2 family proteins are important regulators of apoptotic cell death and form homodimers with other family members Bcl-X L (grey) bound to partner protein via alpha helical region Bound small molecule inhibitor of this interaction

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

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

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”?

Trypsin Inhibitor Protein (BBI) Protease Synthetic interacting motif K i = 9 nM

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

Angiogenin – anti- Angiogenin K D = 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; ChemBioChem 2009

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