Membrane Permeability in Cyclic Peptides is Modulated by Core Conformations.

Area of Science:

• Medicinal Chemistry
• Biophysics
• Drug Discovery

Background:

• Cyclic peptides offer potential for targeting challenging disease-related proteins.
• Current limitations in cyclic peptide therapeutics stem from poor membrane permeability.
• Existing predictive models for peptide permeability are insufficient.

Purpose of the Study:

• To investigate the physicochemical properties governing cyclic peptide membrane permeability.
• To identify novel design strategies for enhancing cyclic peptide permeability.
• To develop improved predictive descriptors for peptide permeability.

Main Methods:

• Synthesis and characterization of a series of cyclic pentapeptides.
• Assessment of membrane permeability using established assays.
• Computational analysis of peptide conformation and physicochemical properties.

Main Results:

• Established criteria for peptide permeability are frequently violated by cyclic peptides.
• A dominant core conformation, stabilized by amide shielding, influences permeability.
• Incorporating polar residues can unexpectedly enhance membrane permeability.
• Core globularity emerged as a key descriptor for predicting permeability.

Conclusions:

• Cyclic peptide design requires a departure from traditional permeability criteria.
• Understanding and manipulating core conformation is crucial for improving peptide delivery.
• Core globularity offers a promising metric for enhancing predictive models of peptide permeability.
• This work facilitates the development of more effective cyclic peptide therapeutics.