The conformational and biological analysis of a cyclic anti-obesity peptide from the C-terminal domain of human growth hormone

The three-dimensional solution structure of antiobesity drug (AOD), a 15-re sidue; disulfide-bonded, cyclic peptide, cyclo(6,13)-H2N-Leu-Arg-lle-Val-Gl n-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, derived from the C-terminal d omain of the human growth hormone (hCH) (residues 177-191) was determined u sing two-dimensional H-1 NMR spectroscopy. AOD stimulates lipolysis and inh ibits lipogenesis, in vitro, in rodent, porcine and human adipose tissues. These biological effects suggest that AOD is a potential therapeutic candid ate for the treatment of obesity. Conformational studies of AOD were conduc ted in aqueous solution and in water/dimethylsulfoxide mixtures. In general , spectral quality was superior in the water/dimethylsulfoxide mixtures. Th e cyclic region of AOD in water/dimethylsulfoxide adopts type I p-turns at residues Ser(8)-Val(9)-Glu(10)-Gly(11) and Ser(12)-Cys(13)-Gly(14)-Phe(15), each preceded by looplike structures. Comparison of the conformation of th is peptide with residues 177-191 in the native hGH protein X-ray crystal st ructure indicates that the synthetic peptide retains some structural simila rity to the intact protein. This study provides evidence that the C-termina l region of hGH is a specific functional domain of the multifunctional hGH protein.