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

Author

Listed:
  • 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)

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

Suggested Citation

  • 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 & David P. Fairl, 2013. "Downsizing a human inflammatory protein to a small molecule with equal potency and functionality," Nature Communications, Nature, vol. 4(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3802
    DOI: 10.1038/ncomms3802
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