Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biophysics

Background:

• N- or C-methylation of cyclic peptides can improve membrane permeability, a crucial factor for drug delivery.
• The precise structural reasons for this permeability enhancement in specific cases remain poorly understood.

Purpose of the Study:

• To investigate the structural basis for how N- or C-methylation influences cyclic peptide membrane permeability.
• To identify key molecular features that correlate with altered membrane transport.

Main Methods:

• Comparative analysis of three-dimensional structures of cyclic peptides from six families.
• Examination of positional isomers differing only in methyl substituent location.
• Correlation of structural features with experimentally determined membrane permeability.

Main Results:

• A single methyl group enhances membrane permeability only when it connects or expands hydrophobic surface patches.
• Positional isomers with identical physicochemical properties exhibit varying membrane permeabilities.
• Permeability differences correlate with the size of the largest continuous hydrophobic surface patch.

Conclusions:

• The local arrangement and expansion of hydrophobic surface patches, rather than overall hydrophobicity, are critical determinants of membrane permeability in methylated cyclic peptides.
• Understanding these local structural effects can guide the design of more permeable peptide-based therapeutics.