This proposal will address the specific objective of selective and quantitative metal cation recognition binding and sensing. The initial phase of the research will focus on chemosensors for CuII, ZnII, and FeIII. Proper regulation of the concentration of these metal cations has serious implications for the maintenance of human health, yet the current methodologies for sensing these analytes is very limited. The scientific objective of this research can be divided into four components that may be independently developed: 1. Development of polypeptides that demonstrate selective coordination to target metal cations. 2. Integration of chemical signal transduction systems that respond to metal cation coordination. 3. Optimization of metal binding and signal transduction processes through combinatorial synthesis and fluorescence screening. 4. Conversion of solution state chemistry to borosilicate glass immobilized peptide arrays. The metallosensors that are described in this proposal are based on synthetic polypeptide structures. We have chosen to use the polypeptide architecture with the incorporation of natural and unnatural metal- coordinating amino acids as the basic framework for metal cation recognition. Polypeptide marry many of the advantages of simple synthetic hosts and complex protein structures while avoiding disadvantages such as restriction to a particular structural type or problems with a labile biomolecule. In the current application, polypeptides are versatile enough to provide metal cation binding selectivity through the variation of both ligand type and geometry, but simple enough to be assembled in large numbers through combinatorial methods. The added advantage of using a totally synthetic system lies in the opportunities for incorporating unnatural metal ligating residues and sensitive optical probes as instrinsic components of each design. Although the current proposal is directed toward the production of chemosensors for three divalent metals, the general concepts that are developed in this research should be applicable to a wide array of target metal cation analytes.
| Pearce, D A; Jotterand, N; Carrico, I S et al. (2001) Derivatives of 8-hydroxy-2-methylquinoline are powerful prototypes for zinc sensors in biological systems. J Am Chem Soc 123:5160-1 |
| Jotterand, N; Pearce, D A; Imperiali, B (2001) Asymmetric synthesis of a new 8-hydroxyquinoline-derived alpha-amino acid and its incorporation in a peptidylsensor for divalent zinc. J Org Chem 66:3224-8 |
