tailieunhanh - Báo cáo khoa học: Site-directed enzymatic PEGylation of the human granulocyte colony-stimulating factor

Poly(ethylene glycol) (PEG) is a widely used polymer employed to increase the circulating half-life of proteins in blood and to decrease their immuno-genicity and antigenicity. PEG attaches to free amines, typically at lysine residues or at the N-terminal amino acid. This lack of selectivity can pres-ent problems when a PEGylated protein therapeutic is being developed, because predictability of activity and manufacturing reproducibility are needed for regulatory approval. | ỊFEBS Journal Site-directed enzymatic PEGylation of the human granulocyte colony-stimulating factor Carlo Maullu1 Domenico Raimondo2 3 Francesca Caboi1 Alejandro Giorgetti2 4 Mauro Sergi1 Maria Valentini2 Giancarlo Tonon1 and Anna Tramontano2 3 5 1 Bio-Ker . c o Sardegna Ricerche Scientific Park Pula Cagliari Italy 2 CRS4-Bioinformatics Laboratory c o Sardegna Ricerche Scientific Park Pula Cagliari Italy 3 Department of BiochemicalSciences A. Rossi Fanelli University of Rome La Sapienza Italy 4 Department of Biotechnology University of Verona Italy 5 Pasteur Institute-Cenci Bolognetti Foundation University of Rome La Sapienza Italy Keywords molecular dynamics PEGylation protein-protein docking site-directed mutagenesis transglutamination Correspondence A. Tramontano Department of Biochemical Sciences A. Rossi Fanelli University of Rome La Sapienza Aldo Moro 5 00185 Rome Italy Fax 39 06 4440062 Tel 39 06 49910556 E-mail Website http These authors contributed equally to this work Received 12 July 2009 revised 14 September 2009 accepted 16 September 2009 doi Poly ethylene glycol PEG is a widely used polymer employed to increase the circulating half-life of proteins in blood and to decrease their immunogenicity and antigenicity. PEG attaches to free amines typically at lysine residues or at the N-terminal amino acid. This lack of selectivity can present problems when a PEGylated protein therapeutic is being developed because predictability of activity and manufacturing reproducibility are needed for regulatory approval. Enzymatic modification of proteins is one route to overcome this limitation. Bacterial transglutaminases are enzyme candidates for site-specific modification but they also have rather broad specificity. The need arises to be able to predict a priori potential PEGyla-tion sites on the protein of interest and especially to be able to design mutants where unique .

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