Scripps Research Scientists Develop Powerful New Methodology for Stabilizing Proteins

Work May Have Broad Implications for Drug Development

Jeffrey Bouley
(FROM Scripps Research Institute) A team of scientists at The Scripps Research Institute has discovereda new way to stabilize proteins—the workhorse biologicalmacromolecules found in all organisms. Proteins serve as the functionalbasis of many types of biologic drugs used to treat everything fromarthritis, anemia, and diabetes to cancer. 
 
As described in the February 4, 2011 edition of the journal Science,when the team attached a specific oligomeric array of sugars called a"glycan" to proteins having a defined structure, the proteins were up to200 times more stable in the test tube. In the body, this stability maytranslate into longer half-lives for therapies, possibly lowering theoverall cost of treatment for certain protein-based drugs and requiringpatients to have fewer injections during a course of treatment. 
  

Thework may have major implications for the drug industry because thereare a large number of protein-based drugs on the market, more inclinical trials, and many more under development worldwide. Nearly allof these protein-based drugs have glycans attached to them and aretherefore called "glycoproteins." Glycoprotein-based drugs can be quiteexpensive to produce and usually need to be administered intravenously.
 
 
Oneof the challenges in producing these drugs has been increasing theirstability, which generally extends their half-life in the bloodstream—issues that the new discovery appears to address directly.
 
"We'venow provided engineering guidelines for glycoprotein stability," saidScripps Research Professor Jeffery W. Kelly, who is chair of theDepartment of Molecular and Experimental Medicine, Lita Annenberg HazenProfessor of Chemistry, and member of The Skaggs Institute for ChemicalBiology at Scripps Research. Kelly led the study with Scripps ResearchAssociate Professor Evan Powers and Staff Scientist Sarah R. Hanson, incollaboration with Research Associates Elizabeth K. Culyba, JoshuaPrice, and colleagues.
 
 
In Search of Stability
 
 
Makingtherapeutic proteins more stable by attaching glycans to them isnothing new. Scientists have known for many years that the human bodywidely modifies proteins in this way after they are made inside cells.By some estimates, as many as a third of all types of proteins in thehuman body are "glycosylated," the scientific name for the processwhereby glycans are attached to proteins. Scientists also know thatthese modifications can be directly linked to protein stability.
 
 
Attaching a glycan to one part of a protein can have a dramatic stabilizing effect, accounting for the difference between it lasting in thebloodstream for a few minutes or a few days. But attaching the sameglycan to another part of the same protein can have a distinctlydifferent destabilizing effect, turning it into the microscopic equivalent of a cooked egg—unfolded and worthless as a medicine.
 
 
Scientistswho work on these sorts of drugs often try to stabilize theirtherapeutic proteins with glycans, but until now nobody understood therules that govern the process—nobody even knew for sure if there weregeneral rules governing it. Researchers have always made suchmodifications through trial-and-error — more of a time-consuming artthan an exact science.
 
 
But now, predicts Powers, "Having a rational design approach will streamline protein drug optimization quite a bit."
 
 
Simple Engineering Rules
 
Thenew research shows simple engineering rules do exist for achievingstability of glycoproteins in the test tube. In the new paper, theScripps Research team showed that scientists could dramaticallystabilize proteins by integrating the standard N-glycan into aparticular part of the protein—a structure known as a "reverse turn"containing a certain combination of amino acids. Reverse turns are foundin the vast majority of proteins, making this methodology broadlyapplicable.
 
 
Thescientists tested their ability to increase the stability of proteinsby creating glycoproteins from proteins that are not normallyglycosylated—leading to increased stabilization in the test tube.These scientists have not yet looked at how long the proteins survive inthe bloodstream—that work is currently under way. But the team isconfident that the principles they discovered will now give scientists anew way to predictably stabilize proteins by design.
 
 
Kellyadded that this portable stabilizing structural module called the"enhanced aromatic sequon" also leads to more efficient production ofglycoproteins by cells, a result that is potentially very important,since glycoproteins remain difficult to produce and purify.
 
 
Inaddition to Kelly, Powers, Hanson, Culyba, and Price, the article,"Protein Native-State Stabilization by Placing Aromatic Side Chains inN-Glycosylated Reverse Turns" is authored by Apratim Dhar, Chi-HueyWong, and Martin Gruebele.
 
 
Thiswork was supported in part by the Skaggs Institute for Chemical Biologyand the Lita Annenberg Hazen Foundation, and funded through grants fromthe National Institutes of Health and the National Science Foundation. 
 

Jeffrey Bouley

Subscribe to Newsletter
Subscribe to our eNewsletters

Stay connected with all of the latest from Drug Discovery News.

November 2022 Issue Front Cover

Latest Issue  

• Volume 18 • Issue 11 • November 2022

November 2022

November 2022