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Published February 16, 2016 | public
Journal Article

Mimicking Protein Functions with Entropically Constrained Peptides


The biological functions of proteins, from molecular recognition to enzymatic activity, depend on the thermodynamic stability of a conformationally constrained folded structure which positions a small number 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 biology 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 defined biological 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 allosteric sites which have revealed new avenues for drug discovery. Recently, discovery of constrained peptides capable of mimicking biological activity on small molecule targets is made possible through the use of suicide substrate activity-based probes. Short constrained peptide motifs capable of activating natural residues and cofactor mimics for nucleophilic attack and decarboxylation have been identified.

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© 2016 Biophysical Society. Published by Elsevier Inc.

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