title: Releasable Conjugation of Polymers to Proteins.
abstract: Many synthetic strategies are available for preparing well-defined conjugates of peptides/proteins and polymers. Most reports on this topic involve coupling methoxy poly(ethylene glycol) to therapeutic proteins, a process referred to as PEGylation, to increase their circulation lifetime and reduce their immunogenicity. Unfortunately, the major dissuading dogma of PEGylation is that, in many cases, polymer modification leads to significant (or total) loss of activity/function. One approach that is gaining momentum to address this challenge is to release the native protein from the polymer with time in the body (releasable PEGylation). This contribution will present the state-of-the-art of this rapidly evolving field, with emphasis on the chemistry behind the release of the peptide/protein and the means for altering the rate of release in biological fluids. Linkers discussed include those based on the following: substituted maleic anhydride and succinates, disulfides, 1,6-benzyl-elimination, host-guest interactions, bicin, β-elimination, biodegradable polymers, E1cb elimination, β-alanine, photoimmolation, coordination chemistry, zymogen activation, proteolysis, and thioesters.
authors.affiliation: †Swiss Federal Institute of Technology Zurich (ETHZ), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Gong
authors.affiliation: †Swiss Federal Institute of Technology Zurich (ETHZ), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
authors.affiliation: ‡Institut National de la Recherche Scientifique (INRS), EMT Research Centre, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Gauthier
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008299:Maleic Anhydrides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009601:Nitroreductases; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011506:Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D019802:Succinic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015091:beta-Alanine / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D001593:Benzyl Compounds; D008299:Maleic Anhydrides; D011108:Polymers; D011506:Proteins; D013438:Sulfhydryl Compounds; D015091:beta-Alanine; C027494:N,N-bis(2-hydroxyethyl)glycine; D011092:Polyethylene Glycols; D019802:Succinic Acid; D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; C021106:azoreductase; D005998:Glycine