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Novel method could improve the performance of proteins used therapeutically
Date:3/9/2011

en), interleukin (IL) 2 (known as aldesleukin and marketed as Proleukin), IL-4, IL-7, IL9-, and IL-15.

"In the course of this work, the first author of the PNAS paper, Maximilian Popp, together with other members of the lab, has put together a nice palette of sortase-based techniques that now allow us to modify a large variety of different proteins, and equip them with properties and behaviors that cannot be easily specified by more standard molecular biological techniques," says Whitehead Member Hidde Ploegh. "I see the value of these approaches first and foremost in their general applicability and ease of use."

IFN-alpha 2 is a cytokine, a hormone-like substance that usually acts on cells other than those that produce the protein. Upon binding the cytokine, the recipient cell responds, for example by starting to divide and proliferate, or by exercising certain functions of benefit to the organism. Like other cytokines used for therapeutic purposes, IFN-alpha 2 can be a finicky drug. It is thermally unstable and must be continuously refrigerated to maintain its potency, a requirement that limits IFN-alpha 2's use in areas with intermittent or no electricity. Also, IFN-alpha 2's relatively short half-life (and resulting rapid clearance from the body) often necessitates frequent injections when the drug is used to treat certain conditions.

To keep therapeutic IFN-alpha 2 active in the body longer, the current strategy is to tack long polyethylene glycol (PEG) chains onto the protein to turn them into effective drugs. This so-called PEGylation not only masks IFN-alpha 2 from the patient's immune system but also increases the time the body needs to break it down. However, because current approaches to PEGylation are not specific, the PEG chains can block or alter the protein's normal binding sitean unintended consequence of this modification that can diminish IFN-alpha 2's potency by as much as 90%.

Seeking greater precisio
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Contact: Nicole Giese
giese@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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