Synthetic approaches to disrupting protein-protein interactions by ybp63883


									Synthetic approaches to disrupting protein-protein interactions

                                 Andrew Hamilton
                                   Yale University
                                  225 Prospect St.
                              New Haven, CT 06520-8107

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.

To top