title: Improving pharmacokinetic properties of adrenocorticotropin by site-specific lipid modification.
abstract: Although many peptides are potentially good therapeutic agents for treating various diseases, only a few have been developed for limited applications. A major shortcoming is that peptides have generally very short serum half lives. In the present study, we use adrenocorticotropin (ACTH) as a model and explore the potential of combining site-specific amino acid substitution and lipid modification to increase the circulating half-lives of peptides. Phe39 of ACTH was substituted by Cys, which has a free sulfhydryl group that can react specifically with iodoacetamide derivatives of lipophilic groups. The biological activities of lipophilized ACTH(F39C)s were higher than native ACTH. Lipophilized ACTH(F39C)s bound more tightly to human serum albumin and cell membranes in vitro and had longer serum half-lives in vivo than native ACTH. These results indicate that the pharmacokinetic properties of peptides can be improved by site-specific substitution with cysteine residues and subsequent conjugation with lipophilic moieties.
authors.affiliation: Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan 300.
authors.forename: Lei
authors.initials: L
authors.lastname: Wan
authors.forename: Yu-Hsien
authors.initials: YH
authors.lastname: Chen
authors.forename: Tse Wen
authors.initials: TW
authors.lastname: Chang
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D003545:Cysteine / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006207:Half-Life; D007273:Injections, Intramuscular; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D013438:Sulfhydryl Compounds; D000324:Adrenocorticotropic Hormone; D003545:Cysteine