Structure-activity relationship and metabolic stability studies of Backbone cyclization and N-methylation of melanocortin peptides

Yaniv Linde, Oded Ovadia, Eli Safrai, Zhimin Xiang, Federico P. Portillo, Deborah E. Shalev, Carrie Haskell-Luevano, Amnon Hoffman, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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 α-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.

Original languageAmerican English
Pages (from-to)671-682
Number of pages12
Issue number5
StatePublished - 2008


  • Backbone cyclization
  • Fmoc chemistry
  • N-methylation
  • Structure activity relationship


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