Grant: Discovery Grants Program - Individual

Here we propose to create a breakthrough technology to present drug target receptors on nano particles for the bio-specific purification of aptamers, i.e. specific peptides drugs, that may be identified and quantified by the analytical power of liquid chromatography electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS), together with 64 bit SQL Server-R computation. Immunoglobulin antibodies like IgG are a class of biological drugs that specifically bind blood ligands, or cell surface receptors, such as the receptors associated with diseases including cancer. Circulating protein ligands such as IgG bind to cell surface receptor targets and may act as highly specific biological drugs in the treatment of disease. There is an urgent need to present ligands such as proteins, antibodies, nucleic acids, or their receptors, on dense, hydrophilic silica nano particles to isolate ligand receptor complexes for analysis by powerful tandem mass spectrometry (LC-ESI-MS/MS) to discover new drugs and new drug targets. Furthermore, there is a need to titre the concentration of specific molecules in circulation and to quantify their binding to the surface of live or fixed cells using powerful LC-ESI-MS/MS or ultra-sensitive enzyme linked mass spectrometric assays (ELiMSA). The specificity of IgG antibodies results from the near random rearrangement of amino acids in the variable domain. Thus it may be possible to leap forward in the production of biological drugs against a protein drug target using random peptide aptamers, or natural peptides from fetal serum, as prototypic biological drugs. A soluble ligand, the soluble portion of the receptor, or receptor associated proteins, may be presented as drug targets to screen the binding of peptide aptamers that might directly serve as prototypic drugs. Conversely, we may use specific ligands such as IgG presented on silica nano particles to capture the receptor protein complex that may be the binding target of therapeutic drugs. Micro particles carrying IgG or oxLDL ligands have been used to capture the Fc and oxLDL receptors and identify and quantify new signaling factors as confirmed by drugs and silencing RNA. Thus we propose that bio-specific purification on silica nano beads interrogated by powerful LC-ESI-MS/MS may isolate new drug targets, screen and reveal new and highly specific biological peptide drugs, and that ELiMSA may be used to rapidly and sensitively titre and quantify the binding to cells, that together will revolutionize our understanding and treatment of disease.