Protein-based drugs are big business, yet biotech and pharma companies often struggle to turn proteins into medicines. One problem is that most proteins are decorated with small groups of sugar molecules, and the wrong sugars can trigger a dangerous immune reaction. Mammalian cell cultures can tack on sugars correctly, but they're finicky and costly. Now researchers have found that yeast promises to be a cheaper way to produce sugared proteins correctly.
Sugars help proteins fold properly and remain stable while in the blood. Immune cells examine these sugars to help them distinguish host proteins from invaders. In both yeast and humans, proteins are produced in the endoplasmic reticulum, decorated with a complex of mannose and other sugars, and eventually shipped to the Golgi apparatus for further processing. In yeast, additional mannose groups are then added. In humans, however, an enzyme called mannosidase chops off the mannose groups, and other enzymes tack on a variety of other sugars.
Several research teams had reasoned that if yeast cells could be engineered to express mannosidase, the cells wouldn't produce the mannose-rich sugar complexes that are so immunogenic to humans. But early attempts failed. Tillman Gerngross of Dartmouth College in Hanover, New Hampshire, and chief scientist at GlycoFi in Lebanon, New Hampshire, and his colleagues suspected that mannosidase in engineered yeast wasn't finding its way to the Golgi apparatus. By fiddling with the cellular postal codes that direct proteins to the appropriate destination, they inserted a more efficient mannosidase and engineered a yeast strain with glycoproteins containing far fewer mannose groups, they reported earlier this year.
Still, their job was only half done; the resulting proteins hadn't been decorated with the sugars commonly found in humans. In the current work, described in the 29 August issue of Science, Gerngross's team linked cell targeting codes to a series of enzymes that attach sugars found on human proteins and then added these genes to mannosidase-producing yeast. The combination worked like a charm, producing large amounts of humanlike proteins.
"This is something people have been trying to do for a long time," says Kelley Moremen, a biochemist at the University of Georgia, Athens. Not only could the new process ease the manufacture of existing protein therapeutics--and thus drop their price--but it could also speed the search for new so-called glycoprotein drugs, because researchers could easily attach different sugars to screen for the most effective combination.