Site-specific polymer attachment to a CCL-5 (RANTES) analogue by oxime exchange.
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.
Shao
Haiyan
H
Gryphon Therapeutics, 600 Gateway Boulevard, South San Francisco, CA 94080, USA.
Crnogorac
Milan M
MM
Kong
Ting
T
Chen
Shiah-Yun
SY
Williams
Jason M
JM
Tack
Janette M
JM
Gueriguian
Vincent
V
Cagle
E Neil
EN
Carnevali
Maia
M
Tumelty
David
D
Paliard
Xavier
X
Miranda
Les P
LP
Bradburne
James A
JA
Kochendoerfer
Gerd G
GG
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
D019380:Anti-HIV Agents; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D010091:Oximes; D011092:Polyethylene Glycols; D005998:Glycine