title: Site-specific polymer attachment to a CCL-5 (RANTES) analogue by oxime exchange.
abstract: A synthetic strategy that allows for the site-specific attachment of polymers such as poly(ethylene glycol) (PEG) to protein pharmaceuticals is described. PEG was attached to a 67-amino acid fully synthetic CCL-5 (RANTES) analogue at its GAG binding site both to reduce aggregation and to increase the circulating lifetime. Effective protection of an Aoaa chemoselective linker during peptide assembly, total chemical protein synthesis, and protein folding was achieved with an isopropylidene group. Mild deprotection of the resulting folded synthetic protein and subsequent polymer attachment occur without interference with the native folded structure and activity.
authors.affiliation: Gryphon Therapeutics, 600 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Shao
authors.forename: Milan M
authors.initials: MM
authors.lastname: Crnogorac
authors.forename: Ting
authors.initials: T
authors.lastname: Kong
authors.forename: Shiah-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: Jason M
authors.initials: JM
authors.lastname: Williams
authors.forename: Janette M
authors.initials: JM
authors.lastname: Tack
authors.forename: Vincent
authors.initials: V
authors.lastname: Gueriguian
authors.forename: E Neil
authors.initials: EN
authors.lastname: Cagle
authors.forename: Maia
authors.initials: M
authors.lastname: Carnevali
authors.forename: David
authors.initials: D
authors.lastname: Tumelty
authors.forename: Xavier
authors.initials: X
authors.lastname: Paliard
authors.forename: Les P
authors.initials: LP
authors.lastname: Miranda
authors.forename: James A
authors.initials: JA
authors.lastname: Bradburne
authors.forename: Gerd G
authors.initials: GG
authors.lastname: Kochendoerfer
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019742:Chemokines, CC / Q000737:chemistry* / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D010091:Oximes / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D017510:Protein Folding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D019380:Anti-HIV Agents; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D010091:Oximes; D011092:Polyethylene Glycols; D005998:Glycine