Q&A: What are pharmacological chaperones and why are they interesting?

What is a chaperone in the context of pharmacology? The term chaperone is borrowed from the name of a class of proteins that function in living cells [1]. Protein molecules are usually only marginally stable under physiological conditions, so some percent of them are often unfolded or misfolded. Such molecules can aggregate with one another, or with properly functioning proteins, with deleterious consequences to the cell. Protein chaperones prevent these unwanted associations by sequestering unfolded and misfolded proteins and providing them with an environment in which they have the opportunity to refold properly. In addition, the interior of a living cell is an extremely crowded environment, in which the concen­ tration of macromolecules may exceed 100 μM [2,3]. As a protein is being synthesized on the ribosome, protein chaperones protect the nascent polypeptide chain from undesirable associations in that crowded environment until it can fold properly. In pharmacology, the role of a chaperone is similar, but instead of being proteins, pharma cological chaperones are small molecules, and instead of assisting in folding, they usually stabilize an already folded macromolecule (usually a protein) by binding to it and stabilizing it against thermal denaturation and proteolytic degradation [4­6]. So a pharmacological chaperone is a chemical chaperone? No, a chemical chaperone is subtly different. Typical chemical chaperones are molecules such as glycerol and trehalose. Pharmacological chaperones are a special subset of chemical chaperones. Molecules like glycerol and trehalose are nonspecific: they bind to, and stabilize, practically any protein and usually do not have a specific binding site. Pharmacological chaperones, on the other hand, are designed specifically to bind to their target protein and, ideally, stabilize only that macromolecule. The difference, therefore, is one of specificity: a chemical chaperone used in vivo would stabilize virtually every macro molecule in the cell. A pharmacological chaperone acts on, at most, only a small number of protein targets. There is a great deal of excitement in the biomedical community these days about pharmacological chaperones because they may be the best approach to treating some serious human diseases, such as cystic fibrosis. Small-molecule chaperones act like molecular glue, holding various parts of the protein structure together through the favorable interactions (electrostatic, van der Waals, and hydrogen bonding) they make with residues in the binding site. Since specific ligand binding sites are often located at the interfaces between protein domains or subdomains [7], such ligands can be particularly effective …