Pharmacological chaperones in the age of proteomic pathology

In the age of “big data,” where thousands of proteins or protein precursors can be interrogated and assembled into large-scale networks, it is still the case that in the setting of disease singular proteins act as hubs in driving pathology (1). Once identified, a pathogenic protein—which can be deficient, dysfunctional, or even overly abundant—becomes a legitimate target for drug discovery. In some cases the protein is an enzyme, receptor, or channel, with easily identifiable and functional binding sites against which pharmaceuticals can be designed with predictable effects (2). In fact, most currently available drugs are directed against this class of proteins. Many pathogenic proteins, however, do not neatly fall into this category. Among the ∼20,000 proteins that make up our proteome, the vast majority falls outside of this rare category, and are therefore not easily “druggable” when implicated in a disease. It is for this reason that various technologies that affect transcription or translation, collectively and loosely called “gene therapy,” have held such high clinical promise. The challenges inherent in gene therapy, for efficacy but mainly for safety, are well documented, and it has yet to transform the pharmaceutical …