This application represents a major new program aimed at the design of synthetic agents that can recognize the exterior surface of proteins. Our primary goal will be to develop a general and modular approach to protein surface recognition that will allow the targeting of a range of different protein surfaces by modifying the recognition characteristics of synthetic receptors. The unique distribution of charged, hydrophobic and hydrophilic groups on the surface of every protein will lead to artificial receptors that bind strongly and selectively. We propose to design and synthesize synthetic receptors that contain multiple peptide loops linked to a central structural core. These agents will contain a large (>400A2) and functionalized surface area to recognize the complementary surface of the target protein. In preliminary results we show that with a modest and unoptimized series of synthetic receptors we can identify potent compounds with different surface characteristics that bind to and influence the reactivity of a range of different protein targets. These include nanomolar inhibitors of the serine proteases chymotrypsin and thrombin and antagonists of growth factor/receptor tyrosine kinase interactions that block cell signaling pathways at 250nM and inhibit the growth of human tumors in nude mouse models. Each of these protein binding agents retains strong affinity for its protein target even in physiological conditions of high ionic strength, suggesting that association involves a combination of hydrophobic and electrostatic interactions. In the proposed project we will modify the central core to allow unsymmetrical disposition of the peptide loops. We will also investigate different loop and core scaffold structures in order to optimize binding to the target proteins. At the same time we will use solution and solid phase methods to develop libraries of our artificial receptors with widely diverse recognition properties that can then be screened for binding activity to different proteins. We will investigate protein surface receptors aimed at the disruption of two therapeutically important serine proteases, thrombin and elastase. We will also target proteins involved in aberrant cell proliferation pathways, including growth factors (such as PDGF, VEGF and EGF).
| Tsou, Lun K; Chen, Chin-Ho; Dutschman, Ginger E et al. (2012) Blocking HIV-1 entry by a gp120 surface binding inhibitor. Bioorg Med Chem Lett 22:3358-61 |
| Tsou, Lun K; Dutschman, Ginger E; Gullen, Elizabeth A et al. (2010) Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold. Bioorg Med Chem Lett 20:2137-9 |
| Ross, Nathan T; Katt, William P; Hamilton, Andrew D (2010) Synthetic mimetics of protein secondary structure domains. Philos Trans A Math Phys Eng Sci 368:989-1008 |
| Jain, Rishi K; Tsou, Lun K; Hamilton, Andrew D (2009) Combined solid/solution phase synthesis of large surface area scaffolds derived from aminomethyl-benzoates. Tetrahedron Lett 50:2787-2789 |
| Margulies, David; Hamilton, Andrew D (2009) Digital analysis of protein properties by an ensemble of DNA quadruplexes. J Am Chem Soc 131:9142-3 |
| Margulies, David; Opatowsky, Yarden; Fletcher, Steven et al. (2009) Surface binding inhibitors of the SCF-KIT protein-protein interaction. Chembiochem 10:1955-8 |
| Wyrembak, Pauline N; Hamilton, Andrew D (2009) Alkyne-linked 2,2-disubstituted-indolin-3-one oligomers as extended beta-strand mimetics. J Am Chem Soc 131:4566-7 |
| Margulies, David; Hamilton, Andrew D (2009) Protein recognition by an ensemble of fluorescent DNA G-quadruplexes. Angew Chem Int Ed Engl 48:1771-4 |
| Gustafsdottir, Sigrun M; Wennstrom, Stefan; Fredriksson, Simon et al. (2008) Use of proximity ligation to screen for inhibitors of interactions between vascular endothelial growth factor A and its receptors. Clin Chem 54:1218-25 |
| Jayawickramarajah, Janarthanan; Tagore, Debarati M; Tsou, Lun K et al. (2007) Allosteric control of self-assembly: modulating the formation of guanine quadruplexes through orthogonal aromatic interactions. Angew Chem Int Ed Engl 46:7583-6 |
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