Sugar Rules For Protein Drugs

A simple list of engineering rules promises to make it easier for drug designers to use sugars to stabilize protein-based drugs (Science, DOI: 10.1126/science.1198461). Boosting the stability of these drugs is expected to increase their half-life and thus potentially decrease how frequently patients must inject them, says Jeffery W. Kelly of Scripps Research Institute, who developed the rules with Scripps colleague Evan T. Powers. The rules point drug designers to specific parts of proteins where they can install standard N-linked sugars to prevent protein aggregation and degradation. Many naturally occurring proteins get a stability boost from sugars that are appended to specific asparagine side chains. But drug designers aiming to mimic that strategy have had to resort to tedious and frustrating trial and error to find appropriate spots to install sugars. Instead, the new rules suggest placing sugars at an asparagine residue in a so-called reverse turn bordered by phenylalanine and threonine residues. This modification stabilizes various kinds of proteins, Kelly and Powers’ team reports. Proteins modified in this way are also more readily manufactured by cells. So the findings should “streamline protein-drug optimization quite a bit,” Powers says.