Among the many mechanisms by which cancer arises, it is now appreciated that inappropriate phosphorylation is a key pathway. Detection agents capable of binding discrete phosphoproteins with high specificity will be important tools for research, diagnostics, and drug discovery. Currently available detection agents are most commonly antibodies or antibody mimetics made using biologic or enzymatic systems. Detection agents that rely on biology or enzymes suffer from several inherent shortcomings that include a restricted biomolecule repertoire that is time-consuming and costly to manufacture. Syntrix proposes to develop a MetaMorph technology that completely bypasses biologic and enzymatic sources with novel synthetic mimetics comprising PNA-cyclopeptide heterotetramers. MetaMorphs will be identified using a novel and purely chemical discovery paradigm termed PNA-display. We hypothesize that PNA-display will permit us to screen very large heterotetramer populations and identify at least moderate- to high-affinity mimetics in a facile system. High-affinity MetaMorphs will provide a phosphoprotein detection capability equivalent to that of antibodies and other biologically derived mimetics, but without the disadvantages. The SBIR Phase I proposal is designed to prove the feasibility of using PNA-display to identify at least moderate affinity MetaMorphs. Demonstrating feasibility will set the stage to move into an aggressive Phase II program to develop high-affinity MetaMorphs capable of detecting phosphotyrosine embedded within peptides having numerous different primary sequences. Such a MetaMorph collection will be capable of detecting hundreds of known and unknown phosphoproteins and will be of significant utility in basic science, diagnostics, and efforts to develop drugs that modulate protein kinases and phosphatases.
| Ye, Guofeng; Schuler, Aaron D; Ahmadibeni, Yousef et al. (2009) Synthesis and evaluation of phosphopeptides containing iminodiacetate groups as binding ligands of the Src SH2 domain. Bioorg Chem 37:133-42 |
