Mimicking protein functions with entropically constrained peptides

Abstract

The biol. functions of proteins, from mol. recognition to enzymic activity, depend on the thermodn. stability of a conformationally constrained folded structure which positions a small no. of amino acid residues in an appropriate position and orientation to carry out their intended function. Most proteins use many weak interactions along a long polypeptide chain to pay the entropic penalty of occupying the native state, though there are examples in biol. of short polypeptides which use a few strong or covalent interactions to stabilize a rigid structure. We have developed a completely synthetic high throughput screening platform capable of identifying conformationally constrained macrocyclic peptides with a well- defined biol. function. Proximity- catalyzed in situ click enables discovery of short constrained peptides capable of binding to a chosen site on a protein surface with no requirements for binding pockets or naturally addressable residues in a manner analogous to monoclonal antibodies. We have successfully targeted post- translational modifications, single amino acid mutations and novel exosites which have revealed new avenues for drug discovery. The modularity of peptide chem. and use of non- natural amino acid residues has enabled the engineering of superb biol., chem. and thermal stability in candidate diagnostic and therapeutic mols. Recently, discovery of constrained peptides capable of mimicking biol. activity on small mol. targets is made possible through the use of suicide substrate activity- based probes in our screens. Short constrained peptide motifs capable of activating natural residues and non- natural cofactor mimics for nucleophilic attack and decarboxylation have been identified.

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