Chemical chaperone

Chemical chaperones are a class of small molecules that function to enhance the folding and/or stability of proteins. Chemical Chaperones are a broad and diverse group of molecules, and they can influence protein stability and polypeptide organization through a variety of mechanisms. Chemical chaperones are used for a range of applications, from production of recombinant proteins to treatment of protein misfolding in vivo.

There are many different small molecules that can function to enhance protein stability and folding, many of them can be broadly grouped into large classes based both on their structure and their proposed mechanism of action. The parameters that define these groups are not strictly defined, and many small molecules that exert a chemical chaperoning effect do not readily fall into one of these categories. For example, the free amino acid arginine is not classically defined as a chemical chaperone, but it has a well-documented anti-aggregation effect.

Cellular osmolytes are polar small molecules that are synthesized or taken up by cells to maintain the integrity of cellular components during periods of osmotic or other forms of stress. Osmolytes are diverse in chemical structure, and include polyols, sugars, methylamines, and free amino acids and their derivatives. Examples of these include glycerol, trehalose, trimethylamine n-oxide (TMAO), and glycine. Despite being most active at relatively high concentrations, osmolytes don’t display any effects on normal cellular processes – for this reason, they are also commonly referred to as “compatible solutes”. Osmolytes exert their chaperoning effects indirectly by changing the interaction of the protein with solvent, rather than through any direct interaction with the protein. Unfavorable interactions between proteins and osmolytes increases the solvation of the protein with water. This increased hydration favors more compact polypeptide conformations, in which hydrophobic residues are more tightly sequestered from polar solvent. Thus, osmolytes are thought to work by structuring partially folded intermediates and thermodynamically stabilizing folded conformations to a greater extent than unfolded conformations.

Chemical compounds that have varying degrees of hydrophobicity that still are soluble in aqueous environments can act as chemical chaperones as well. These compounds are thought to act by binding to solvent-exposed hydrophobic segments of unfolded or improperly folded proteins, thereby “protecting” them from aggregation. 4-phenylbutyrate (PBA) is a prominent example of this group of compounds, along with lysophosphatidic acids and other lipids and detergents.

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