Therapeutic Development of Two Pathogenic Amyloids
- Author(s): Zhao, Anni
- Advisor(s): Eisenberg, David S
- et al.
Amyloids are structured aggregates formed by misfolded proteins. Research has shown 25+ diseases associated with amyloid deposits in vivo. No cure has yet been developed for the majority of these conditions and the development of disease-modifying drugs has been disappointing. In the past year, several pharmaceutical companies have simultaneously withdrawn drug trials because of the ineffective clinical results. However, these treatments have been developed based on the molecular understanding of amyloid proteins from a few decades earlier. The amyloid field has made promising advancements in the past several years that offer potential for new therapeutic strategies. We now know that a subset of amyloidosis is caused by the deposition of the mature fibrils. Others are caused by the low molecular weight oligomers formed along the fibrillation pathway. Atomic views of these amyloid species were made available with the first steric zipper structure published in 2005 revealing the fibril spine and a cylindrin structure published in 2012, revealing the core of a toxic oligomer. These structures provide opportunities for new therapeutic strategies against amyloid diseases. In the course of my PhD work, I have investigated two amyloid protein systems. The first project focused on amyotrophic lateral sclerosis, a progressive motor neuron disease caused by oligomer formation of the amyloid protein superoxide dismutase I. I identified a region in the protein that is particularly important for the cytotoxicity, and solved its crystal structure. This work revealed a potential drug target for amyotrophic lateral sclerosis, a painful disease with no available treatment option. The second project focuses on an extracellular peptide whose fibril formation drastically enhances HIV infection. I developed inhibitors that prevented fibril formation and reduced HIV infection rate in a functional assay. Importantly, these inhibitors were designed based on the steric zipper structure, common to many amyloid fibrils. As such, this approach has the potential to be adapted to the other 25+ amyloid systems.