According to recent news, Irish scientists have finally generated a crystal structure for the PEGylated Protein. It is the most comprehensive structural study yet and it will open insights of how such molecules improve injectable therapies.
Protein PEGylation is a technique to improve the properties of injectable therapeutic proteins; PEG stand for “polyethylene glycol”, a synthetic polymer that is attached to proteins. The PEG chain boosts a therapeutic Protein’s size and retention in bloodstream. Since the 1970s, PEGylated proteins have improved the treatment of diseases such as hepatitis C, leukemia, Crohn’s disease and arthritis. 
Yet the structure of the proteins remained elusive. Now, a group in NUI Galway in Ireland has generated the first crystal structure of a Protein modified with a single PEG chain.
Peter Crowley , chemist in NUI Galway, Ireland and senior author of the study said that most people would say it is impossible to crystallize a PEGlyated Protein but it is not so. We have successfully generated the crystal and it behaves as a long random structure, something like a piece of spaghetti swirling around in sauce.
PEG is a synthetic polymer of chemical structure –CH2CH2O-. It can be made in different sizes and branched forms are possible. Crowley explains why deciphering the structure matters.
Crowley said there are still questions about how PEG increases the size of a Protein and how PEG might stick to the Protein surface. One model is that the PEG acts like a ‘shroud’ and wraps around the Protein. In the alternative model known as “dumbbell” the PEG avoids the Protein and behaves almost independently. The crystal structure that their team made supports the dumbbell model. Everyone might imagine the PEG is like a parachute dangling off the Protein.
Protein Structure
The Protein is structured as an orthogonal shaped structure with intertwined double helices and large pores that house the PEG chains.
Crowley explained, “The pores in the crystal are just the right size to accommodate the PEG. It seems therefore, that it might also be possible to engineer Protein assemblies using PEG chains of different sizes.”
Gianfranco Pasut, pharmaceutical scientist at the University of Padua in Italy said that EG does not have a 3-dimensional fixed structure and so it is difficult to have a technique that is able to visualize its conformation when it is linked to a Protein. He further added that PEG has many positive effects, such as Protein half-life prolongation in vivo by reducing kidney clearance, but it usually reduces the Protein activity as consequence to its steric entanglement towards the Protein receptor.
Half-life prolongation and immunogenicity reduction are better with larger PEGs but also activity reduction is more marked with bigger PEGs. Knowing how PEG is structured around a Protein will surely help to design better conjugates.
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