BPS 2024
Synthetic Alpha-sheet Peptides for Treatment of Amyloid Diseases
Jeff Posakony
Director of Translational Chemistry, AltPep Corporation
ABSTRACT
Amyloidogenic peptides and proteins are associated with over 50 diseases linked to neurodegenerative and systemic disorders, including Alzheimer’s Disease, Parkinson’s Disease, Type 2 diabetes, systemic amyloidosis, etc. that affect over 1 billion people worldwide. These peptides and proteins can undergo conformational changes from their native structure to alpha-sheet conformations which self-aggregate to form soluble oligomeric species and then transition to amyloid fibrils/fibrillar plaques. Regardless of the function and native structure of an amyloidogenic protein, the corresponding fibrils form a cross-β sheet structure. Studies have shown that toxicity associated with amyloid diseases is due to the toxic soluble oligomeric species, which are considered early molecular triggers of disease, rather than fibrillar plaques.
In the case of Alzheimer’s Disease, many experimental treatments have been based on the “amyloid hypothesis”, using anti-amyloid monoclonal antibodies that target extracellular amyloid plaques, fibrils and protofibrils. These treatments have shown no or limited benefit as the intervention takes place long after the damage has occurred. Damage due to the toxic soluble oligomers of amyloid-beta peptide may cause damage to the brain 10 to 20 years before clinically evident disease
The Daggett Research Group at the University of Washington approached amyloid diseases in a novel way. By developing and employing innovative computer simulation techniques, they discovered a new protein structure, called alpha-sheet, linked to toxic soluble oligomers. The discovery of this structure and its association with toxicity became the basis for AltPep’s proprietary technology. AltPep’s platform is designed to specifically target alpha-sheet toxic oligomers through therapeutic peptide candidates with stable alpha-sheet structures. An overview of AltPep’s therapeutic peptide program will be presented.
BIO
Throughout his chemistry career, Jeff has been involved in multidisciplinary teams in basic research, and development of therapeutics and diagnostics in areas ranging from RNA structural biology, cancer, heart disease, antivirals, immunomodulators, antinocioceptive agents, and amyloid diseases. After his PhD, he spent 13 years as a bench chemist in academic/government-sponsored research and moved to the biotech industry more than 10 years ago. He now oversees a team dedicated to late-stage lead selection, drug substance and drug product/pharmaceutics development for AltPep Corporations key peptide therapeutic candidates.