Issue Date: March 7, 2011
Balancing Act Reduces Peptide Aggregation
Highly hydrophobic domains make a protein or peptide more susceptible to aggregation. Zhongping Tan, Shiying Shang, and Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center report a strategy by which they reduce this aggregation by balancing hydrophobicity and electrostatic repulsion, using a major segment of human erythropoietin (hEPO) as an example (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1100195108). The Sloan-Kettering team modified a portion of hEPO by attaching arginine groups to two lysine residues and to two glutamic acids via cleavable allylic ester (shown) or carbamate linkers. This approach allowed the researchers to modify the hydrophobicity and the net charge without altering the underlying amino acid sequence. The allylic linkers are stable under solid-phase synthesis conditions, but they can be removed under mild conditions by palladium-catalyzed deprotection. Peptides containing the arginine tags aggregated much less than did the native peptide and variants containing conventional protecting groups. Such a strategy could help improve the shelf life of synthetically prepared protein and peptide therapeutics, the researchers say.
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