High Throughput, Late-Stage Drug Diversification in Neurodegenerative Disease

Abstract

Protein-Protein Interactions are the foundation of many regulatory processes in physiological systems. Perturbations in these processes such as mutations or conditional cellular stress can cause the mutation or misfolding of essential proteins, leading to aberrant Protein-Protein Interactions (aPPIs) that have cascading negative effects on essential biochemical processes. aPPIs are implicated as the leading cause and progressor of neurodegenerative diseases, particularly Parkinson’s, Alzheimer’s, ALS, and Huntington’s Disease. While many attempts at therapeutic treatments for neurodegenerative diseases have emerged in the last 30 years, the modulation of disease related aPPIs has proven to be a demanding and complex task as the interactions between relevant proteins occur between a large variety of chemical moieties and protein surface areas. Chemically diverse synthetic libraries of organic compounds have recently been employed to nullify aPPIs in vitro and in vivo. Previous libraries of compounds have proven both synthetically difficult and relatively non-scalable. In this work, we present a family of Oligopyridyl (OP) compounds that are synthetically trivial, scalable, and potent antagonists of relevant aPPIs in the human brain.