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

Reid, Robert C., Yau, Mei-Kwan, Singh, Ranee, Hamidon, Johan K., Reed, Anthony N., Chu, Peifei, Suen, Jacky Y., Stoermer, Martin J., Blakeney, Jade S., Lim, Junxian, Faber, Jonathan M. and David P. Fairlie, (2013) Downsizing a human inflammatory protein to a small molecule with equal potency and functionality. Nature Communications, 4 2802: 1-9. doi:10.1038/ncomms3802

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Author Reid, Robert C.
Yau, Mei-Kwan
Singh, Ranee
Hamidon, Johan K.
Reed, Anthony N.
Chu, Peifei
Suen, Jacky Y.
Stoermer, Martin J.
Blakeney, Jade S.
Lim, Junxian
Faber, Jonathan M.
David P. Fairlie,
Title Downsizing a human inflammatory protein to a small molecule with equal potency and functionality
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2013-11-21
Sub-type Article (original research)
DOI 10.1038/ncomms3802
Open Access Status File (Publisher version)
Volume 4
Issue 2802
Start page 1
End page 9
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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 <500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Authors' prepress title: "Downsizing a human Inflammatory Protein to a Small Molecule with Equipotent Functions".

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 14 times in Scopus Article | Citations
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Created: Sun, 24 Nov 2013, 19:54:34 EST by Dr Martin Stoermer on behalf of Chemistry, Department of