Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

Robert C. Reid, Mei-Kwan Yau, Ranee Singh, Johan K. Hamidon, Anthony N. Reed, Peifei Chu, Jacky Y. Suen, Martin J. Stoermer, Jade S. Blakeney, Junxian Lim, Jonathan M. Faber and David P. Fairlie ()
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Robert C. Reid: Institute for Molecular Bioscience, The University of Queensland
Mei-Kwan Yau: Institute for Molecular Bioscience, The University of Queensland
Ranee Singh: Institute for Molecular Bioscience, The University of Queensland
Johan K. Hamidon: Institute for Molecular Bioscience, The University of Queensland
Anthony N. Reed: Institute for Molecular Bioscience, The University of Queensland
Peifei Chu: Institute for Molecular Bioscience, The University of Queensland
Jacky Y. Suen: Institute for Molecular Bioscience, The University of Queensland
Martin J. Stoermer: Institute for Molecular Bioscience, The University of Queensland
Jade S. Blakeney: Institute for Molecular Bioscience, The University of Queensland
Junxian Lim: Institute for Molecular Bioscience, The University of Queensland
Jonathan M. Faber: Institute for Molecular Bioscience, The University of Queensland
David P. Fairlie: Institute for Molecular Bioscience, The University of Queensland

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight

Date: 2013
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DOI: 10.1038/ncomms3802

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