The purpose of this project is to develop a RULE-BASED APPROACH for the design and synthesis of proteomimetics of the alpha-helix and in doing so establish to what extent the structural and functional role of the alpha-helix can be reproduced with non-natural molecules in a PREDICTABLE manner We will focus on developing aromatic oligoamide proteomimetics (compounds that mimic the secondary structure from which they are derived) of one of the dominant secondary structural motifs observed in proteins the alpha-helix. Helices play a key role in mediating many protein-protein interactions, they interact with proteins and contribute residues to the resulting complex that form part of a catalytic site and they operate within the context of an entire protein structure as scaffolding upon which other helices, sheets, turns and coils pack to generate an active 3D structure. We will therefore: (i) develop a general approach for the inhibition of alpha-helix mediated protein-protein interactions, (ii) develop proteomimetics that can bind to an inactive protein and restore catalytic activity (iii) develop proteomimetics that can be covalently incorporated into the primary sequence of a protein without abolishing its function. This will lead to immense opportunities for development of new therapeutics and proteins with new functionality. More significantly, re-engineering nature to the extent of replacing whole segments of protein backbone with non-natural prostheses as proposed here will begin to answer the fundamental question: Is the astonishing structural and functional complexity achieved through precise secondary and tertiary organisation of primary protein structure confined to sequences of alpha-amino acids?
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