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On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.
Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat
Selective, On-Resin <i>N</i>‑Methylation of Peptide <i>N</i>‑Trifluoroacetamides
Mild and efficient methods for site-specific methylation of peptide backbone amides are important tools for chemists seeking to modulate the pharmacokinetic properties of peptide drugs. The Mitsunobu reaction was used to selectively methylate <i>N</i>-trifluoroacetamide (Tfa) protected peptides on-resin. The Tfa group was removed quickly and completely by reduction with excess NaBH<sub>4</sub>, and it was shown to be orthogonal to many of the protecting groups used in solid-phase peptide synthesis
Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides
The effect of peptide-to-peptoid
substitutions on the passive membrane
permeability of an <i>N</i>-methylated cyclic hexapeptide
is examined. In general, substitutions maintained permeability but
increased conformational heterogeneity. Diversification with nonproteinogenic
side chains increased permeability up to 3-fold. Additionally, the
conformational impact of peptoid substitutions within a β-turn
are explored. Based on these results, the strategic incorporation
of peptoid residues into cyclic peptides can maintain or improve cell
permeability, while increasing access to diverse side-chain functionality
On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
Backbone N-methylation is common among peptide natural products and has a significant impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was determined by backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (MW = 755) with three N-methyl groups, showed an oral bioavailability of 28% in rat
Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators
The chemokine receptor CXCR7 is an
attractive target for a variety
of diseases. While several small-molecule modulators of CXCR7 have
been reported, peptidic macrocycles may provide advantages in terms
of potency, selectivity, and reduced off-target activity. We produced
a series of peptidic macrocycles that incorporate an N-linked peptoid
functionality where the peptoid group enabled us to explore side-chain
diversity well beyond that of natural amino acids. At the same time,
theoretical calculations and experimental assays were used to track
and reduce the polarity while closely monitoring the physicochemical
properties. This strategy led to the discovery of macrocyclic peptide–peptoid
hybrids with high CXCR7 binding affinities (<i>K</i><sub>i</sub> < 100 nM) and measurable passive permeability (<i>P</i><sub>app</sub> > 5 × 10<sup>–6</sup> cm/s).
Moreover, bioactive peptide <b>25</b> (<i>K</i><sub>i</sub> = 9 nM) achieved oral bioavailability of 18% in rats, which
was commensurate with the observed plasma clearance values upon intravenous
administration