Synthetic approaches to disrupting protein-protein interactions Andrew Hamilton Yale University 225 Prospect St. New Haven, CT 06520-8107 USA Andrew.Hamilton@yale.edu In this lecture we will describe a program aimed at the design of synthetic agents that can recognize the exterior surface of proteins. The unique distribution of charged, hy- drophobic and hydrophilic groups on the surface of every protein oﬀers the potential that well-designed artiﬁcial receptors will bind strongly and selectively. By analogy to the antigen combining site of the antibody FAB fragment, we have constructed a family of artiﬁcial receptors that contain a large and functionalized surface area to recognize the complementary surface of the target protein. We will describe several diﬀerent strategies for targeting such proteins as cytochrome c and growth factors. The designed compounds take advantage of complementary hy- drophobic and electrostatic interactions to achieve high aﬃnity and selectivity in binding to protein targets. From this strategy we have identiﬁed molecules that block protein- protein interactions and others that can be developed into arrays for the detection of proteins in solution. In some cases binding of the synthetic receptor leads to a signiﬁ- cant decrease in the thermal stability of the protein. This has led us to develop a novel strategy for modulating protein function that involves selective denaturation followed by facilitated proteolytic cleavage.
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