Protein-protein interactions (PPIs) are responsible for regulating various important functions within living organisms. Compounds which can selectively modulate aberrant PPIs are novel therapeutic candidates for treating human diseases. Whilst PPIs have traditionally been considered as “undruggable”, research in this area has led to the emergence of several effective methodologies for inhibiting PPIs. One such methodology is peptide stapling, which involves constraining a short peptide into its native alpha-helical form by covalently linking two of its amino acid side-chains.<br/>Our work involves the synthesis of strained dialkyne linkers containing heteroatoms for their use in metal-free strain-promoted click-reaction, thus eliminating the use of cytotoxic Cu(I) catalyst. Different substituted variants of Sondheimer-Wong diyne were synthesised. These were then applied to undergo metal-free stapling of diazido peptides with an aim that the functionalisation of the linker will impart novel properties to the stapled peptide modifying its solubility, binding affinity with protein, and cell permeability (Figure). These stapled peptides were then applied to target the p53-MDM2 interaction as an anti-cancer therapy.<br/>Computational studies and kinetic experiments have been carried out in order to investigate the reactivity variation of functionalised strained linkers towards click reaction.

Strain-promoted double-click functionalised stapled peptides for inhibiting protein-protein interactions

255th National Meeting (2018)

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