Jeffery W. Kelly - The Scientific Origins of Drugs that Slow Neurodegeneration скачать в хорошем качестве

Jeffery W. Kelly - The Scientific Origins of Drugs that Slow Neurodegeneration

Jeffery W. Kelly, Lita Annenberg Hazen Professor of Chemistry at The Scripps Research Institute, received his Ph.D. in organic chemistry from the University of North Carolina (1986), and post-doctoral training at The Rockefeller University (1986-89). The central theme of Kelly lab research is to understand the kinetic competition between protein folding, misfolding, and aggregation— the latter process being associated with neurodegenerative diseases. Knowledge gained from these investigations is used to conceive of new therapeutic strategies for diseases of protein conformation, including amyloid diseases. The Kelly lab discovered the first drug to slow the progression of a human amyloid disease by inhibiting protein aggregation–the blockbuster drug tafamidis marketed by Pfizer. To do this, he translated a genetic observation regarding transthyretin amyloidosis into a mechanistic biochemical understanding of amyloid disease prevention (imposing kinetic stabilization on the native state). Tafamidis inhibits transthyretin aggregation by binding to and kinetically stabilizing the native tetrameric transthyretin conformation, dramatically slowing tetramer dissociation, the rate-limiting step of transthyretin aggregation. Tafamidis was the first drug to demonstrate the importance of protein aggregation as a driver of human amyloid diseases. The Kelly lab is currently pursuing the development of a light chain kinetic stabilizer in light chain amyloidosis clinical trials, as well as preclinical development of autophagy activators. An author of more than 400 papers (ISI h-index = 107), Professor Kelly is an elected member of the National Academy of Sciences, the American Academy of Arts and Sciences. His contributions have been recognized by awards including the Wolf Prize in Chemistry, the Breakthrough Prize in Life Sciences, The Stein and Moore Award of the Protein Society, the Jacob and Louise Gabbay Award in Biotechnology and Medicine, and the Ross Prize in Molecular Medicine. Kelly has placed 46 trainees in academia and over 70 trainees in the biotechnology and pharmaceutical industries. Abstract: “The Scientific Origins of Drugs that Slow Neurodegeneration” Strong published human genetic evidence supports the hypothesis that protein aggregation causes neurodegeneration mediated by amyloid diseases. There are now 10 regulatory agency–approved drugs that slow neurodegeneration by modulating protein aggregation, providing compelling pharmacological evidence that protein aggregation drives the degeneration of nervous systems and other organ systems. Our laboratory had the privilege of discovering the first regulatory agency–approved drug that slows the progression of an amyloid disease–transthyretin amyloidosis, the third most prominent amyloid disease behind Alzheimer’s and Parkinson’s. The first half of the seminar will focus on the evidence demonstrating that the transthyretin tetramer-stabilizing, anti-aggregation drugs that we conceived and developed by structure-based design and the interallelic transsuppressor mutations we characterized in compound heterozygotic patients that protect against transthyretin amyloid disease function identically–both slow tetramer dissociation and subsequent transthyretin aggregation. The transthyretin native state kinetic stabilizer tafamidis, sold by Pfizer and discovered by our laboratory, is currently being used in more than 60,000 transthyretin amyloidosis patients to extend their lifespan and healthspan by slowing amyloid disease progression. The next section of the seminar will focus on describing the mechanisms of action of the other FDA-approved drugs that modulate protein aggregation and what we have learned from these medicines about the etiology of human amyloid diseases–there is a common structure-proteotoxicity hypothesis that emerges. In the final section of the presentation, I will describe our current efforts on the discovery of mTOR-inhibitor independent autophagy activators for the general amelioration of neurodegenerative diseases. Learn more about The Welch Conference: https://welch1.org/conference/confere...