title: Self-assembled nanostructures of long-acting GnRH analogs modified at position 7.
abstract: It is well known that GnRH analogs can self-assemble into amyloid fibrils and that the duration of action of GnRH analogs depends on the ability of the amyloid to slowly release active peptides. The aim of this study was to investigate the influence of the amino acid residues at position 7 of GnRH analogues on peptide self-assembly. It was found that the dominant shape of the nanostructure can be changed when the structures of the residues at position 7 differ significantly from that of leucine in Degarelix. When the backbone length was extended (peptide 9), or the side chain of the residue at position 7 was replaced by an aromatic ring (peptide 6), or the rotation of the amide bond was restricted (peptide 8), the nanostructure changed from fibrils to vesicles. The results also indicate that the increasing hydrophilicity had little influence on the nanostructure morphology. In addition, a suitable release rate was found to play a more important role for the duration of the peptide action by maintaining the equilibrium between the drug concentration and the persistent release time, while the nanostructure shape was found to exert little influence on the duration of the peptide action.
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, China.
authors: Ning
authors: N
authors: Zhou
authors: Xing
authors: X
authors: Gao
authors: Yujian
authors: Y
authors: Lv
authors: Junping
authors: J
authors: Cheng
authors: Wenxia
authors: W
authors: Zhou
authors: Keliang
authors: K
authors: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006727:Hormone Antagonists / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D006727:Hormone Antagonists; D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone
keywords: GnRH; long-acting; nanostructures; peptides; self-assembly