Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- and C-Methylations Fine-Tune Conformation and Properties

Abstract

Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

“…Unfortunately, their effect is non-linear and highly site-dependent. 24,26–30 The cell permeability of cyclic peptides often drops with increasing peptide size. 31 Nevertheless, some larger cyclic peptides can display internal conformational changes, which are crucial for membrane permeability.…”

Effect of Flexibility, Lipophilicity, and the Location of Polar Residues on the Passive Membrane Permeability of a Series of Cyclic Decapeptides

“…Similarly, we could not detect correlations between ensemble 3D PSA and permeability in our study of four semipeptidic tetramers. 29 Instead of focusing on the PSA, Hoang et al 30 calculated the largest connected hydrophobic surface area for 16 molecules categorized into six series of varied sizes (including mainly hexa-, heptapeptides, and two undeca-peptides). Within each series of 2−4 peptides, the hydrophobic surface area correlated well with permeability.…”

Passing the Barrier – How Computer Simulations Can Help to Understand and Improve the Passive Membrane Permeability of Cyclic Peptides

“…The shown structures are snapshots from our extensive MD simulations representing the differences in the hydrogen-bond patterns of the two compounds in apolar environments. [23]…”

“…2) leads to a 'permeability cliff' in experimental permeability assays. [23] Using a combination of NMR and MD Fig. 1.…”