Proteins perform the majority of the complex functions critical to life. To do so, they have to fold into their functional shapes through transitory intermediates. These short-lived intermediates are highly reactive and disordered and, when the protein folding process goes awry, they can aggregate and create harmful biology that plays a role in a variety of disease pathways—for example, in neurodegeneration, cancer, cardiovascular disease, diabetes, and cystic fibrosis. Research in the past few years has elucidated with increasing precision how the abnormally configured amyloidogenic proteins in Alzheimer's and Parkinson’s diseases— found in fibrils and plaques—assemble through toxic oligomer intermediates that play a direct role in neurodegeneration and neuronal death in these diseases.
This relatively recent understanding—that intermediate protein oligomers are toxic entities directly responsible for neurotoxicity—has defined a new approach to treating a central molecular cause of neurodegeneration. Yet the fleeting and ephemeral nature of protein intermediates presents a fundamental challenge to conventional drug discovery approaches.
Characterizing and suppressing protein intermediates is one of the most challenging problems in drug discovery for scientists working with protein assembly reactions because these protein forms cannot simply be put in a bottle and analyzed in isolation. The dominant approach to drug discovery depends on identifying drugs that interact directly with a single target, using assays that isolate and stabilize the target so that it can be studied directly in a test tube or petri dish. But targeting the complex, highly interconnected process of amyloid formation in neurodegenerative diseases requires a different approach to measure, assay, and analyze the proteins during their evolving compositions—from their formation to their disappearance. This requires targeting a network of interactions that is fundamentally different from the conventional single-target discovery approach.
To address this challenge, we have built a drug discovery platform on the foundation of our scientists’ discoveries involving the physics and biochemistry of protein assembly dynamics. Wren’s technology platform enables the analysis of how oligomer intermediates interact and evolve in complex disease processes. Our network-centric paradigm for drug discovery allows us to see the oligomer protein production pathway for the first time and discover small molecules that can block their generation with precision.