Download ORGANIC CHEMISTRY SEMINAR Professor Jeff Kelly Biological and Chemical Approaches to Adapt

ORGANIC CHEMISTRY SEMINAR
Professor Jeff Kelly
Scripps Research Institute
Biological and Chemical Approaches to Adapt
Proteostasis to Ameliorate Protein Aggregation Diseases
The cellular protein homeostasis, or proteostasis network, regulates
proteome function by controlling ribosomal protein synthesis, chaperone and
enzyme mediated protein folding, protein trafficking, proteindegradation and
the like. Stress responsive signaling pathways match proteostasis network
capacity with demand in each subcellular compartment to maintain cellular
homeostasis. The beginning of the seminar will focus on how the
proteostasis network can be adapted through unfolded protein response
arm-selective signaling to alleviate gain-of-toxic-function diseases where
excessive secretion of misfolding and aggregation of proteins leads to the
amyloid diseases. The second part of the seminar will focus on a chemical
strategy to achieve protein homeostasis, wherein small molecule kinetic
stabilizers produced by structure-based drug design are employed to halt
the progression of peripheral neuropathy in the human disease familial
amyloid polyneuropathy linked to transthyretin amyloidogenesis. I will
explain how delineating themolecular mechanism of transthyretin
aggregation linked to pathology led to a regulatory agency approved drug.
Since this is the first pharmacologic evidence supporting the amyloid
hypothesis, the notion that protein aggregation causes degeneration of the
heart and the nervous system, the last part of the seminar will focus on what
we have learned about the etiology of these diseases vis-à-vis a successful
clinical trial.
Tuesday, February 25, 3:30 pm
Room 1315 Chemistry