Synthesis directed at the disruption of protein-protein interactions - asthma and cancer related targets

School Colloquium

Two projects will be described, both relating to synthetic efforts to develop small molecules to disrupt protein-protein interactions (PPIs) of potential medicinal importance.

The first PPI we have been investigating is that between Immunolobulin E (IgE) (a protein found e.g. in the blood) and its high affinity receptor FceRI (a membrane-bound protein found e.g. on the surface of mast cells and basophils). This PPI is central to the allergic signal transduction cascade and so is a key target for potential anti-asthma therapeutics. Proof of principle that this strategy can be effective, and does not suffer from unacceptable side-effects, comes from the successful clinical use of the monoclonal antibody Omalizumab (Xolair^) which is indicated for severe persistent asthma and operates by sequestering IgE in the blood and preventing binding to FceRI. However, its high cost and non-oral mode of delivery has fuelled interest in the development of alternative, small molecule antagonists of this PPI. We have been investigating approaches to disrupting this PPI based on both constrained peptides based on a hot spot epitope of IgE¹ and based on a natural product antagonist, aspercyclide A.^2,3

The second PPI we have been investigating is that between the Nuclear Receptor (NR) Liver Receptor Homologue-1 (LRH-1) and its various co-activator and co-repressor proteins such as the transcription activator Peroxisome Proliferator-Activated Receptor-γ Co-activator (PGC)-1a. The regulation of transcription by these complexes has potential therapeutic benefit in the context of breast cancer where LRH-1 has been implicated as having a role in modulating estrogen signalling.⁴ The PPI centres on an interaction between an LXXLL a-helical motif in the co-activator and a complimentary groove in the co-activator binding domain (AF2) of the NR. We have been investigating approaches to disrupting this PPI based on rational design of a new a-helix mimetic motif.

References

1.         D.A. Offermann, J.E. McKendrick, J.J.P. Sejberg, B. Mo, M.D. Holdom, B.A. Helm, R.J. Leatherbarrow, A.J. Beavil, B.J. Sutton, A.C. Spivey, 'Synthesis and Incorporation into Cyclic Peptides of Tolan Amino Acids and their Hydrogenated Congeners: Construction of an Array of A-B-loop Mimetics of the Cε3 Domain of Human IgE', J. Org. Chem. 2012, 77, ASAP.
2.         J.L. Carr, D.A. Offermann, M.D. Holdom, P. Dusart, A.J.P. White, A.J. Beavil, R.J. Leatherbarrow, S.D. Lindell, B.J. Sutton^, A.C. Spivey 'Total Synthesis of (+/-)-Aspercyclide A and its C19 Methyl Ether' Chem. Comm. 2010, 1824-1826.
3.         J.L. Carr, J.J.P. Sejberg, F. Saab, M.D. Holdom, A.M. Davies, A.J.P. White, R.J.Leatherbarrow, A.J. Beavil, B.J. Sutton, S.D. Lindell, A.C. Spivey, 'Synthesis of the C19 Methyl Ether of Aspercyclide A via Germyl-Stille Macrocyclisation and ELISA Evaluation of Both Enantiomers Following Optical Resolution', Org. Biomol. Chem. 2011, 9, 6814-6824.
4.            Thiruchelvam, P.T.;  Lai, F.F.; Hua, H.; Thomas, R.S.; Hurtado, A.; Hudson, W.; Bayly,A.R.; Kyle, F.J.; Periyasamy, M.; Photiou, A.; Spivey,A.C.; Ortlund,E.A.; Whitby,R.J.; Carroll, J.S.; Coombes, R.C.; Buluwela, L.; Ali, S. 'The liver receptorhomolog-1 regulates estrogen receptor expression in breast cancer cells' Breast Cancer Res. Treat. 2010, 127, 385-396.