Highly luminescent lanthanide complexes provide attractive design opportunities for the development of potential clinical and biological diagnostic probes. This proposal describes the design strategy for synthesizing polypeptides of 12-20 residues that could be used for such applications. Peptides offer advantages over other chelate molecules by being biocompatible, water soluble and easily modified. Since Ln3+ ions bind well to Ca2+- binding sites, a short loop region of a Ca2+-binding protein provides an initial target sequence. Modular components that are based on key requirements of luminescent lanthanide complexes will be engineered into the starting sequence to optimize for tight lanthanide ion binding and intense fluorescence emission. Unnatural amino acids with expanded chelate arms will provide a saturated coordination sphere for Tb3+ or Eu3+, thus avoiding coordinated waters from deactivating luminescence. Appropriate chromophores along the peptide chain will act as antennae to sensitize Ln3+ emission through energy transfer. Parallel synthesis with these modular components via solid phase techniques will be used to screen for the most promising candidates. Modification of a promising sequence with recognition elements for peptide-peptide, peptide-protein or peptide-drug interactions could then lead to efficient and adaptable sensors of biological or clinical targets.
