Life at the interface: Byron Caughey's search for prion disease inhibitors through chemistry, structure, and cell...

The search for effective therapeutics that can bring hope to patients and families affected by rare prion diseases is ongoing. Self-propagating, misfolded proteins underlie a broad range of neurodegenerative disorders that include prion diseases as well as more common conditions such as Parkinson's and Alzheimer's disease. Byron Caughey was a pioneer in the field of prion therapeutic discovery. His seminal contributions in drug development included elucidating disease biochemistry, understanding the need to target conformational changes, and developing cell-free conversion assays to monitor protein misfolding in real time. These advances laid the foundation for therapeutic strategies aimed at preventing, slowing or reversing the conversion of native protein into a pathogenic, seed-competent conformer and/or its assembly into amyloid fibrils. Within the Caughey laboratory, small molecule inhibitors targeting the misfolded prion, the process of conversion and aggregation, or stimulating disassembly were studied intensively. More recent approaches targeted the relocation, removal or downregulation of the normal protein substrate. These efforts in combination with high-resolution structural characterization of the infectious prions now offer new opportunities for intelligent drug design. Equally important to drug discovery have been advances in the development of sensitive and reliable methods to detect the agent and its clearance, which is necessary to validate that putative treatments are efficacious. Herein, we highlight 4 decades of Byron Caughey's contributions and dedication to the search for anti-prion therapeutics.