Passive Membrane Permeability in Cyclic Peptomer Scaffolds Is Robust to Extensive Variation in Side Chain...

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biophysics

Background:

• Cyclic peptides are explored as drug scaffolds for membrane permeability.
• Cyclic peptomers combine peptide and N-alkylglycine (peptoid) features, offering diverse chemical properties.

Purpose of the Study:

• To synthesize and evaluate cyclic peptomer libraries for membrane permeability.
• To investigate the impact of side chain and backbone variations on permeability.

Main Methods:

• Split-pool synthesis techniques were used to create cyclic peptomer libraries.
• Parallel artificial membrane permeability assay (PAMPA) was employed to measure permeability coefficients (Papp).

Main Results:

• Nearly 50% of synthesized cyclic peptomers exhibited high membrane permeability (Papp > 1 × 10^-6 cm/s).
• Specific backbone geometries enhanced permeability by promoting stable intramolecular hydrogen bonds.
• High permeability was achievable across a broad lipophilicity range.

Conclusions:

• Hexameric cyclic peptomers demonstrate good passive membrane permeability despite structural diversity.
• Cyclic peptomers represent a viable scaffold for developing drugs with enhanced membrane penetration.