How structural features influence the biomembrane permeability of peptides

Area of Science:

• Pharmacology
• Biophysics
• Drug Delivery

Background:

• Peptide-based therapeutics show promise for AIDS, cardiovascular, and CNS disorders.
• Clinical application of peptides is hindered by poor bioavailability and inefficient cell membrane transport.
• The precise mechanisms governing peptide transport across biological membranes remain poorly understood.

Purpose of the Study:

• To investigate the relationship between peptide structure and transport across biological membranes.
• To elucidate the factors limiting peptide bioavailability and therapeutic efficacy.
• To identify potential strategies for enhancing peptide drug delivery.

Main Methods:

• Systematic preparation of peptides varying in chain length, lipophilicity, and amide bond number.
• In vitro assessment of peptide permeability using Caco-2 cell monolayers (intestinal model).
• In vivo studies in rat intestinal and blood-brain barrier models to evaluate peptide absorption.

Main Results:

• Peptide transport is primarily determined by the energy required for desolvation of polar amides.
• Active, secretory transport systems in intestinal and brain endothelial cells act as additional barriers.
• These systems exhibit substrate specificity, saturation, and inhibition, returning absorbed peptides to the lumen.

Conclusions:

• Understanding peptide desolvation energy is crucial for optimizing drug delivery.
• Active secretory transport mechanisms significantly impede peptide bioavailability.
• Targeting these transport systems may enhance the clinical utility of peptide therapeutics.