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.

Strategic Approaches to Optimizing Peptide ADME Properties

“…Some approaches not only improve stability, but also enhance other ADME properties, e.g., cyclization can increase stability and permeability; conjugation to macromolecules can improve stability and reduce renal clearance (70)(71)(72)(73)(74)(75). It is important to maintain potency and avoid toxicity while improving stability and ADME properties of peptides.…”

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…N-methylation has been applied to obtain analogs of numerous peptides, leading in some cases to derivatives with enhanced affinity and selectivity [115]. On the other hand, the additional methyl group causes steric hindrance, introducing some rigidity into the peptides, which can at times prevent bioactivity [116]. A good strategy is to perform N-methyl scans on peptide sequences of interest, in order to systematically explore the influence on the conformation of the peptide and discover the analog with the highest affinity and bioavailability.…”

Peptidic modulators of protein‐protein interactions: Progress and challenges in computational design

“…Shorter peptides and peptidomimetics mimicking the endogenous peptidic ligands of some GPCRs are under active development. 21,54 Integrins are a family of heterodimeric cell-surface receptors that regulate cell attachment and response to the extracellular matrix. Many integrins recognize a sequence in the matrix protein that contains the core amino-acid triplet, ''Arg-Gly-Asp'' (RGD).…”