pH Controlled Transient Cyclization of Peptides for Increased Stability towards Oral Delivery

Area of Science:

• Biochemistry
• Drug Delivery
• Medicinal Chemistry

Background:

• Peptides are effective therapeutics for oncology and diabetes but face challenges in oral delivery due to low bioavailability.
• New chemical strategies are required to overcome the degradation of peptides in the gastrointestinal tract for oral administration.

Purpose of the Study:

• To develop a novel pH-responsive linearization strategy for transient peptide protection and extended half-life.
• To create stable, orally deliverable peptide analogues using ester-based linkers and cyclization.

Main Methods:

• Development of ester-based responsive linkers enabling O-to-N acyl shift for pyroglutamoyl (pGlu) or diketopiperazine (DKP) formation.
• Cyclization of peptides using copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) after linker coupling.
• Assessment of peptide stability in simulated gastric fluid (SGF) across various pH levels and evaluation of cyclic peptide linearization.

Main Results:

• Successfully designed and synthesized pH-responsive cyclic peptides that remain stable at low pH and linearize at neutral pH.
• Demonstrated the ability of the developed chemical strategy to protect peptides and enable their linearization.
• Generated PYY3-36 analogues exhibiting pH-responsive linearization, indicating enhanced stability.

Conclusions:

• pH-responsive linearization is a viable strategy for transient peptide protection, extending half-life and improving stability.
• The developed ester-based linkers and cyclization methods facilitate oral peptide delivery by protecting peptides in the stomach.
• This approach holds promise for developing orally administered peptide therapeutics, particularly for diseases like cancer and diabetes.