title: Separation of fast from slow anabolism by site-specific PEGylation of insulin-like growth factor I (IGF-I).
abstract: Insulin-like growth factor I (IGF-I) has important anabolic and homeostatic functions in tissues like skeletal muscle, and a decline in circulating levels is linked with catabolic conditions. Whereas IGF-I therapies for musculoskeletal disorders have been postulated, dosing issues and disruptions of the homeostasis have so far precluded clinical application. We have developed a novel IGF-I variant by site-specific addition of polyethylene glycol (PEG) to lysine 68 (PEG-IGF-I). In vitro, this modification decreased the affinity for the IGF-I and insulin receptors, presumably through decreased association rates, and slowed down the association to IGF-I-binding proteins, selectively limiting fast but maintaining sustained anabolic activity. Desirable in vivo effects of PEG-IGF-I included increased half-life and recruitment of IGF-binding proteins, thereby reducing risk of hypoglycemia. PEG-IGF-I was equipotent to IGF-I in ameliorating contraction-induced muscle injury in vivo without affecting muscle metabolism as IGF-I did. The data provide an important step in understanding the differences of IGF-I and insulin receptor contribution to the in vivo activity of IGF-I. In addition, PEG-IGF-I presents an innovative concept for IGF-I therapy in diseases with indicated muscle dysfunction.
authors: Roche pRED, 4070 Basel, Switzerland. friedrich.metzger@roche.com
authors: Friedrich
authors: F
authors: Metzger
authors: Waseem
authors: W
authors: Sajid
authors: Stefanie
authors: S
authors: Saenger
authors: Christian
authors: C
authors: Staudenmaier
authors: Chris
authors: C
authors: van der Poel
authors: Bettina
authors: B
authors: Sobottka
authors: Angelika
authors: A
authors: Schuler
authors: Mandy
authors: M
authors: Sawitzky
authors: Raphael
authors: R
authors: Poirier
authors: Dietrich
authors: D
authors: Tuerck
authors: Eginhard
authors: E
authors: Schick
authors: Andreas
authors: A
authors: Schaubmar
authors: Friederike
authors: F
authors: Hesse
authors: Kurt
authors: K
authors: Amrein
authors: Hansruedi
authors: H
authors: Loetscher
authors: Gordon S
authors: GS
authors: Lynch
authors: Andreas
authors: A
authors: Hoeflich
authors: Pierre
authors: P
authors: De Meyts
authors: Hans-Joachim
authors: HJ
authors: Schoenfeld
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D006207:Half-Life; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009140:Musculoskeletal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin