Solid state stabilization of proteins by sugars: Why size and flexibility matter

Protein therapeutics play an important role in modern day medicine. They are of immense value in the treatment of diseases like diabetes, breast cancer, and rheumatoid arthritis. However, an important limitation of many protein therapeutics, which are often in aqueous solution, is their limited shelf life. Proteins can degrade and lose their functionality in a multitude of ways. How and how fast proteins degrade depends on the characteristics of the protein as well as on the stresses the protein is exposed to. Drying proteins in the presence of sugars can increase protein shelf life, even though the drying process itself can lead to protein degradation. Sugars therefore have to provide protection to the protein during drying and sufficiently increase storage stability of the dried product. For a sugar to act as a good protein stabilizer, the sugar needs to be able to interact closely with the protein, inhibit mobility of the protein on a molecular level, and the sugar should not react with the protein. Not all sugars meet all of these criteria and therefore not all of them are equally suitable as protein stabilizers. We showed that the ability of a sugar to stabilize proteins is related to their size and molecular flexibility. In general, smaller and molecularly flexible sugars are better protein stabilizers because they can interact with the protein more closely. This knowledge can aid in improving storage stability of these important protein drugs