title: Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides.
abstract: Backbone cyclization (BC) and N-methylation have been shown to enhance the activity and/or selectivity of biologically active peptides and improve metabolic stability and intestinal permeability. In this study, we describe the synthesis, structure-activity relationship (SAR) and intestinal metabolic stability of a backbone cyclic peptide library, BL3020, based on the linear alpha-Melanocyte stimulating hormone analog Phe-D-Phe-Arg-Trp-Gly. The drug lead, BL3020-1, selected from the BL3020 library (compound 1) has been shown to inhibit weight gain in mice following oral administration. Another member of the BL3020 library, BL3020-17, showed improved biological activity towards the mMC4R, in comparison to BL3020-1, although neither were selective for MC4R or MC5R. N-methylation, which restrains conformational freedom while increasing metabolic stability beyond that which is imparted by BC, was used to find analogs with increased selectivity. N-methylated backbone cyclic libraries were synthesized based on the BL3020 library. SAR studies showed that all the N-methylated backbone cyclic peptides demonstrated reduced biological activity and selectivity for all the analyzed receptors. N-methylation of active backbone cyclic peptides destabilized the active conformation or stabilized an inactive conformation, rendering the peptides biologically inactive. N-methylation of backbone cyclic peptides maintained stability to degradation by intestinal enzymes.
authors.affiliation: Institute of Chemistry, Safra Campus, Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Linde
authors.forename: Oded
authors.initials: O
authors.lastname: Ovadia
authors.forename: Eli
authors.initials: E
authors.lastname: Safrai
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Federico P
authors.initials: FP
authors.lastname: Portillo
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000818:Animals; D002460:Cell Line; D003500:Cyclization; D006801:Humans; D053486:Melanocortins / Q000737:chemistry* / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism*; D011487:Protein Conformation; D044101:Receptors, Melanocortin / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D053486:Melanocortins; D019151:Peptide Library; D010456:Peptides, Cyclic; D044101:Receptors, Melanocortin