Todd Gibson, PhD 2005

Thesis Title: Modulating protein aggregation with targeted, surface tension-modifying compounds

Aggregation of proteins is becoming increasingly problematic as more industries explore the manufacture of protein-based products, such as monoclonal-antibody pharmaceuticals and recombinant enzymes. Also, the aggregation of amyloid-forming proteins is involved in the etiology of neurodegenerative and other diseases. Some of these diseases, such as Alzheimer's and Huntington's, are age-related and have become more prevalent as the average life-span increases. For these reasons, there is a growing need for effective methods to control protein aggregation.

In Alzheimer's disease, the peptide beta-amyloid (Aβ) aggregates to form highly-structured, insoluble amyloid fibrils, and this aggregation process is associated with neuronal toxicity. Hence, numerous research efforts have focused on the discovery and development of compounds that alter Aβ aggregation.

We investigated a hybrid compound-inhibitor strategy involving the use of peptides or derivitized peptides, which contain a recognition domain that associates with full-length Aβ and a disrupting domain that alters aggregation. A significant benefit of hybrid compounds over other aggregation-altering approaches is that they have activity at low (equimolar) concentration ranges; we hypothesize that this is because recognition domain affinity localizes the hybrid compound near the aggregating protein. Effective hybrid compounds increase the rate of Aβ aggregation and protect against Aβ toxicity.

In this study, we elucidated a probable explanation for the mechanism of acceleration of Aβ aggregation by hybrid compounds, and we developed and tested novel hybrid compounds in support of this explanation; we propose that hybrid compounds accelerate aggregation because of their ability to increase the solvent surface tension. We also extended the ideas used in the development of Aβ hybrid compounds to develop a novel hybrid compound that inhibits insulin aggregation and reduces surface tension. Prevention of insulin aggregation is useful in maintaining stability of therapeutic insulin for diabetes treatment. Also, control of insulin aggregation could be helpful in treatment of insulin-related amyloidosis, a disease that involves aggregation and deposition of insulin amyloid fibrils.