A Long-Acting, Mono-PEGylated Human Growth Hormone Analog Is a Potent Stimulator of Weight Gain and Bone Growth in Hypophysectomized Rats
| Autor: | Elizabeth A. Chlipala, Sharon J. Carlson, Mary S. Rosendahl, Darin J. Smith, George N. Cox, Daniel H. Doherty |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Hypophysectomy medicine.medical_treatment Drug Evaluation Preclinical Biology Weight Gain Article Polyethylene Glycols Rats Sprague-Dawley Endocrinology In vivo Internal medicine medicine Animals Potency chemistry.chemical_classification Bone growth Bone Development Tibia Human Growth Hormone In vitro Rats Amino acid Somatropin Treatment Outcome chemistry Delayed-Action Preparations PEGylation Half-Life |
| Zdroj: | Endocrinology. 148:1590-1597 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2006-1170 |
| Popis: | Recombinant human Growth Hormone (GH) is used to treat growth hormone deficiency in children and adults, and wasting in AIDS patients. GH has a circulating half-life of only a few hours in humans and must be administered to patients by daily injection for maximum effectiveness. Previous studies showed that longer-acting forms of GH could be created by modification of GH with multiple 5 kDa amine-reactive polyethylene glycols (PEGs). Eight of nine lysine residues and the N-terminal amino acid were modified to varying extents by amine-PEGylation of GH. The amine-PEGylated GH product comprised a complex mixture of multiple PEGylated species that differed from one another in mass, in vitro bioactivity and in vivopotency. In vitro bioactivity of GH was reduced 100- to 1,000-fold by extensive amine-PEGylation of the protein. Here we describe a homogeneously modified, monoPEGylated GH protein that possesses near complete in vitro bioactivity, a long half-life and increased potency in vivo. The monoPEGylated GH was created by substituting cysteine for threonine-3 (T3C) of GH, followed by modification of the added cysteine residue with a single 20 kDa cysteine-reactive PEG. The PEG-T3C protein has an approximate 8-fold longer half-life than GH following sc administration to rats. Every other day or every third day administration of PEG-T3C stimulates increases in body weight and tibial epiphysis growth comparable to that produced by daily administration of GH in hypophysectomized rats. Long-acting, monoPEGylated GH analogs such as PEG-T3C are promising candidate for future testing in humans. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|