Orally Absorbed Cyclic Peptides.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Peptides and proteins generally lack oral bioavailability due to size and polarity, limiting their therapeutic use.
• Existing active transport mechanisms are inefficient for larger peptides, necessitating new delivery strategies.
• Systematic evaluation of peptides >500 Da is crucial for understanding oral absorption parameters.

Purpose of the Study:

• To identify parameters influencing oral bioavailability of cyclic peptides.
• To explore the chemical properties that enable oral absorption of cyclic peptides in mammals.

Main Methods:

• Synthesized and analyzed 125 cyclic peptides (4-37 amino acids).
• Assessed oral absorption in mammals.
• Evaluated key physicochemical properties: molecular weight, lipophilicity, hydrogen bonding, rotatable bonds, polar surface area.

Main Results:

• Cyclic peptides demonstrated oral absorption in mammals, defying traditional bioavailability limits.
• Cyclization protects peptides from degradation and influences conformation, impacting absorption.
• Reduced hydrogen bond donors and flexibility generally correlated with improved oral absorption.

Conclusions:

• Cyclization is a viable strategy to enhance peptide oral bioavailability.
• Specific physicochemical properties of cyclic peptides are critical for their absorption.
• Findings challenge conventional drug-likeness rules for oral absorption.