Backbone Cyclic Peptidomimetic Melanocortin-4 Receptor Agonist as a Novel Orally Administrated Drug Lead for Treating Obesity

Abstract

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.

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

“…17 It has become clear that proteinpeptide interactions are very abundant in the cell and estimates suggest they represent 15-40% of all interactions, 18 making peptide discovery and development of wide applicability and interest. Cyclic peptides [19][20][21][22] and other modified peptides 23,24 can be highly potent as well as selective, providing a compromise between structural preorganization and sufficient flexibility to mold to a target surface and maximize binding interactions. There is much evidence that despite having molecular masses well above Lipinski's rule constraints, cyclic peptides and other macrocycles can possess drug-like physicochemical and pharmacokinetic properties such as good solubility, lipophilicity, metabolic stability and bioavailability.…”

“…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).…”

“…For example, cyclic peptides [19][20][21][22]110 and peptides that include non-native residues such as N-methylated 111,112 or D-amino acids, 42 may improve stability, cell permeability and efficacy of natural peptide leads. Sequence-based tools or knowledgebased protein force fields cannot be applied to these compounds, which are no longer merely short proteins.…”

Peptide Design Strategies for G‐Protein Coupled Receptors (GPCR)

“…This has been primarily due to the same chemistry as the typical amide bond formation of a growing peptide chain. Backbone cyclization (BC) is one of the approaches that utilizes atoms in the backbone (N and/or C) of a target linear peptide through a linker to form a ring and shown to dramatically enhance the metabolic stability and pharmacological stability of peptides [96]. Advantage of BC over other peptide cyclization methods is that they use the backbone atoms leaving the side chain intact, which are essential for biological activity at the receptor.…”

“…Advantage of BC over other peptide cyclization methods is that they use the backbone atoms leaving the side chain intact, which are essential for biological activity at the receptor. Utilizing this approach, Hess et al [96] have synthesized a library of backbone cyclic analogs where the bridge was formed connecting the N-terminus to the N of the C-terminal Gly building unit by a dicarboxylic acid spacer. All the peptides in the library consist of the same parent sequence, but differ in ring size.…”