title: Binding of phosphorylated peptides and inhibition of their interaction with disease-relevant human proteins by synthetic metal-chelate receptors.
abstract: The modulation of biological signal transduction pathways by masking phosphorylated amino acid residues represents a viable route toward pharmacologic protein regulation. Binding of phosphorylated amino acid residues has been achieved with synthetic metal-chelate receptors. The affinity and selectivity of such receptors can be enhanced if combined with a second binding site. We demonstrate this principle with a series of synthetic ditopic metal-chelate receptors, which were synthesized and investigated for their binding affinity to phosphorylated short peptides under conditions of physiological pH. The compounds showing highest affinity were subsequently used to inhibit the interaction of the human STAT1 protein to a peptide derived from the interferon-gamma receptor, and between the checkpoint kinase Chk2 and its preferred binding motif. Two of the investigated ditopic synthetic receptors show a significant increase in inhibition activity. The results show that regulation of protein function by binding to phosphorylated amino acids is possible. The introduction of additional binding sites into the synthetic receptors increases their affinity, but the flexibility of the structures investigated so far prohibited stringent amino acid sequence selectivity in peptide binding.
authors.affiliation: Institute for Organic Chemistry, University of Regensburg, Regensburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Riechers
authors.forename: Andreas
authors.initials: A
authors.lastname: Grauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Ritter
authors.forename: Bianca
authors.initials: B
authors.lastname: Sperl
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
mesh_terms: D064447:Checkpoint Kinase 2; D002614:Chelating Agents / Q000378:metabolism; D006801:Humans; D008670:Metals / Q000378:metabolism*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002614:Chelating Agents; D008670:Metals; D010455:Peptides; D050794:STAT1 Transcription Factor; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases