Redox-active Chemical Chaperones for Therapeutic Applications to Protein Misfolding Diseases
Proteins are made up of a large number of amino acids linked together. Folding is the process by which the polypeptide chain folds into a three-dimensional structure called the native structure, which allows the protein molecule to acquire its original biochemical function and activity. Proteins can also form non-natural structures called misfolded structures during the folding process. Misfolded proteins are not only inactive, but are also pathogenic to cause misfolding diseases through amyloid formation.
In recent years, proteins have attracted attention as pharmaceuticals such as antibody drugs. Therefore, the technology and science of efficiently folding proteins into their natural structures is an important research theme that is relevant not only to biology but also to pharmacy and medicine.
Protein folding proceeds through multiple interactions such as hydrogen bonding and hydrophobic interactions within the polypeptide chain. In our laboratory, we are focusing on disulfide bond formation, in particular, to develop small molecule compounds that promote protein folding. Folding accompanied by disulfide bond formation is called oxidative protein folding and is observed in many membrane proteins, extracellular secretory proteins, and antibodies used in pharmaceuticals.
Oxidative protein folding in cells is promoted by redox-active enzymes such as protein disulfide isomerase (PDI). The enzyme binds 1:1 to a client denatured protein and facilitates its folding. Small molecular weight compounds that mimic the thiol/disulfide structure in the active center of PDI have been developed and reported to have a folding-promoting function, but all of them are required to add an excess amount relative to the client protein.
We have recently succeeded in developing pMePySS, the first synthetic molecule that promotes folding with high efficiency by adding only one equivalent to the client protein. Compared to the conditions under which conventional compounds are used, pMePySS was found to promote folding at less than 1/10 of the amount added, indicating that pMePySS is 10 times more active than the existing compounds.
pMePySS also showed high efficiency for insulin folding with the addition of one equivalent amount, indicating that it is also useful for the synthesis of pharmaceutical proteins. These results are expected to contribute to the development of therapeutics against misfolding diseases such as Parkinson's disease, Alzheimer's disease, and type 2 diabetes caused by structurally aberrant proteins, in addition to improving the efficiency of synthesis of protein drugs such as insulin and antibody drugs. (Chemical Science 2023)