title: Stability, permeability and growth-inhibitory properties of gonadotropin-releasing hormone liposaccharides.
abstract: OBJECTIVE
  In this study we aimed to address the poor drug-like properties of Gonadotropin-Releasing Hormone (GnRH) peptide through modification with lipids and carbohydrates.
  
  
  METHODS
  GnRH peptide was conjugated to 2-amino-D,L-octanoic acid (C8) and 2-amino-D,L-dodecanoic acid (C12) in monomer and dimer, along with (6-9) or without (2-5 and 11) a glucose moiety. Peptides were tested for their biological activity using different tumour cell lines. The toxicity of the constructs was evaluated in peripheral blood mononuclear cells (PBMC).
  
  
  RESULTS
  All (glyco)lipopeptides showed improved metabolic stability in Caco-2 cell homogenates. Those with single lipid moiety (2, 4 and 8) exhibited prodrug-like properties. Permeability across Caco-2 cell monolayers was enhanced in the dimer C8-modified (glyco)lipopeptide (3) and the lipopeptide with C12 inserted mid-sequence (11). Most of the constructs showed moderate-to-high antiproliferative activity against GnRH-receptor positive DU145 and OVCAR-3 cells (up to 60%). Compound 11 was the most effective with IC50 = 26.4 ± 1.07 μg.ml(-1), which was comparable to triptorelin (25.1 ± 1.14 μg.mL(-1)). The sensitivity of OVCAR-3 cells to the effect of all analogues except for 11 decreased significantly in estrogen-reconstituted media. Only compounds 2, 4, 5 and 8 showed a steroid-dependent effect in DU145 cells. No compounds exhibited significant toxicity on PBMCs.
  
  
  CONCLUSIONS
  These results indicated lipidation and glycosylation improves the druggability of GnRH and could lead to an increased direct antitumour activity in some hormone dependent and independent reproductive cancers.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, 4072, Queensland, Australia.
authors.forename: Daryn
authors.initials: D
authors.lastname: Goodwin
authors.forename: Pegah
authors.initials: P
authors.lastname: Varamini
authors.forename: Pavla
authors.initials: P
authors.lastname: Simerska
authors.forename: Istvan
authors.initials: I
authors.lastname: Toth
mesh_terms: D000586:Amination; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002210:Caprylates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006031:Glycosylation; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007850:Lauric Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010539:Permeability; D011966:Receptors, LHRH / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; D007850:Lauric Acids; D011966:Receptors, LHRH; C030358:lauric acid; D007987:Gonadotropin-Releasing Hormone; C031492:octanoic acid