RESUMO
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 (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
Assuntos
Peptídeos/química , Peptídeos/farmacologia , Peptoides/química , Peptoides/farmacologia , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Peptoides/administração & dosagem , Peptoides/farmacocinética , Ratos , Ratos WistarRESUMO
The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-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 ß-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.
Assuntos
Células Epiteliais/efeitos dos fármacos , Peptídeos/farmacologia , Permeabilidade/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Células Epiteliais/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Relação Estrutura-AtividadeRESUMO
Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.