Molecular Recognition in Biomimetic Receptors

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The primary aims of this application will be to develop synthetic agents that can recognize the exterior surface of proteins and disrupt clinically important protein-protein interactions. We will exploit the unique distribution of charged, hydrophobic and hydrophilic groups on the surface of every protein to identify artificial receptors that bind selectively and potentially disrupt biological function. A central feature of our approach will be the design of synthetic agents that contain a large (>400 Angstrom 2) and functionalized surface area to recognize the complementary surface of the target protein. In the previous project period we have shown that this strategy can lead to protein binding agents that show high affinity (nM-pM) for specific protein targets, are selective among a range of different proteins, are effective in conditions of high salt concentration and can disrupt protein-protein interactions in vivo. Within these primary goals we will have the following specific aims: Specific Aim 1- To develop synthetic receptors that bind with high affinity and selectivity to growth factor proteins (including PDGF, VEGF, EGF and FGF) involved in aberrant cell proliferation pathways. Specific Aim 2- To develop synthetic agents that bind to the surface of cytochrome c and disrupt its interaction with Apaf-1 to form the apoptosome. We will target the exterior surface of cytochrome c that is involved in its interactions with protein partners. Specific Aim 3- To develop synthetic ligands that bind selectively to the surface of phosphorylated proteins and signal their presence through fluorescence emission changes. We will develop binding agents that target the phosphotyrosine groups on the surface of activated signaling proteins, such as Bcr-Abl, STAT3 and Src using a cyclic tris-biphenylamide scaffold. Specific Aim 4- To develop arrays of fluorescent binding agents that can be used to detect proteins with different surface properties and to optimize binding selectivities for other targets. We will develop solution and solid phase arrays of fluorescent protein binding agents that show distinctive patterns of quenching in the presence of proteins with different surface recognition characteristics.