Faculty

Protein-protein interactions form the scaffold on which signaling networks are built and are the driving force behind the aggregation of misfolded proteins. Identifying small molecules that inhibit protein-protein interactions, however, has been difficult. One reason for this is that the contact area between proteins is large (~1000 square angstroms), while the molecular weight (less than 1000 Da) and surface area (typically a few dozen square angstroms) of drug-like molecules is low. Low molecular weight facilitates favorable pharmacokinetic properties, but also limits the effectiveness of these molecules as inhibitors of large-scale interactions.

The key innovation in our approach is that small molecule-based inhibitors of protein-protein interactions do not have to act alone; they function as part of a complex with an abundant cellular chaperone. For example, we have synthesized a bifunctional molecule that binds to the amyloid beta (Abeta) peptide, which is implicated in Alzheimer's disease. Abeta self-associates into oligomers that are highly neurotoxic. Small molecule strategies to inhibit Abeta-Abeta interactions have been largely unsuccessful, partly due to the low mass of the pharmacophores. To address this limitation, we generated bifunctional molecules that bind with high affinity to both Abeta and the chaperone, FKBP. The combination of the bifunctional drug and FKBP has a composite molecular weight of over 13,000 Da. These drug-protein complexes are now potent inhibitors of Abeta aggregation (IC50 ~ 50 nM) and block Abeta neurotoxicity. In another example, we are using combinations of small molecules and heat shock proteins (HSPs) to identify and destroy potentially cytotoxic protein aggregates. This method marks a deviation from traditional small molecule design and, instead, evokes kinship with vaccine strategies in which an organism's own cells/proteins are mobilized to construct a desired response.

For more information, check out the Gestwicki Lab website.

Awards

McKnight Foundation Brain Disorders Award (with A. Lieberman and W. Pratt)
Biological Sciences Scholar (University of Michigan)
Helen Hay Whitney Foundation Post-Doctoral Fellowship
Sigrid Leirmo Award (Departmental Service; UW Madison)
NIH Biotechnology Training Program Pre-Doctoral Fellowship

Representative Publications

1. Chang, L., Bertelsen, E.B., Wisen, S., Larsen, E.M., Zuiderweg, E.R.P, Gestwicki, J.E., "High throughput screen for small molecules that modulate the ATPase activity of the molecular chaperone, DnaK", Anal. Biochem., 2008, 372, 167.

2. Gestwicki, J.E., Marinec, P.S., "Chemical contorl over protein-protein interactions: beyond inhibitors", Combi. Chem. High Throughput Screen, 2007, 10(8), 667.

3. Evans, C.G., Wisen, S., Gestwicki, J.E., "Heat shock proteins 70 and 90 inhibit early stages of amyloid beta aggreation in vitro", 2006, 281, 33182.

4. Gestwicki, J.E., Crabtree, G.R. and Graef, I.A., "Harnessing chaperones to generate small molecule inhibitors of amyloid beta aggregation", Science, 2004, 306, 865.

5. Gestwicki, J.E. and Keissling, L.L., "Inter-receptor communication through arrays of bacterial chemoreceptors", Nature, 2002, 415, 81.