title: Downsizing a human inflammatory protein to a small molecule with equal potency and functionality.
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.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Mei-Kwan
authors.initials: MK
authors.lastname: Yau
authors.forename: Ranee
authors.initials: R
authors.lastname: Singh
authors.forename: Johan K
authors.initials: JK
authors.lastname: Hamidon
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Reed
authors.forename: Peifei
authors.initials: P
authors.lastname: Chu
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stoermer
authors.forename: Jade S
authors.initials: JS
authors.lastname: Blakeney
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Faber
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D015926:Complement C3a / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D011951:Receptors, Complement / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D018836:Inflammation Mediators; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a