Adventures in Non-Covalent Chemistry: From DNA Bases to alpha-helices Seminar

Modern challenges in materials and biological science require the ability to understand and manipulate non-covalent chemistry. This presentation will discuss two bio-inspired approaches under development in our group to achieve this objective focused on materials assembly and inhibition of protein-protein interactions.

'Smart materials' or stimuli responsive polymers (i.e. those that change their properties in response to temperature, solvent, light or chemical additives) are highly sought after.  Their properties like those of biopolymers, are governed by the non-covalent interactions that give rise to defined folded or aggregated architectures.  Inspired by the assembly of DNA, the first part of this presentation will focus on our efforts to design hydrogen-bonding motifs^[1] and their incorporation into supramolecular polymers (Fig la). ^[2]

In the case of α-helix mediated PPIs, a number have been shown to represent attractive targets for the development of anticancer therapeutics, however what is not clear is how to do this using a small molecule, given that it must cover 800-1100Ų of a protein surface and complement the discontinuous projection of hydrophobic and charged domains over a flat or moderately convex surface.  The second part of this presentation will focus on our efforts to develop robust synthetic methods for synthesis of Proteomimetics (Fig. 1b) and the associated screening efforts against several targets including p53/hDM2 and Mcl-1/NOXA-B. ^[3-4]

 References

[1] M.L. Pellizzaro, K.A. Houton, A.J. Wilson, Chem. Sci., 2013, 4, 1825-1829

[2] A.Gooch, C.Nedolisa, K. Houton, C.I.Lindsay, A.Saini, A.J.Wilson, Macromolecules, 2012, 4723

[3] V. Azzarito, K.Long, N.S.Murphy and A.J.Wilson, Nature Chem, 2013, 5, 161-173

[4] F. Campbell, J.P.Plante, T.A.Edwards, S.L.Warriner, A,J,Wilson, Org. Biomol. Chem, 2010, 8, 2344-2351