Data-driven synthesis of proteolysis-resistant peptide hormones

Area of Science:

• Biochemistry
• Endocrinology
• Drug Discovery

Background:

• Peptide hormones regulate physiology but face therapeutic limitations due to rapid proteolysis.
• Developing proteolysis-resistant peptide analogs is crucial for advancing peptide-based therapeutics.

Purpose of the Study:

• To establish a data-driven synthesis strategy for creating proteolysis-resistant peptide hormone analogs.
• To apply this strategy to oxyntomodulin (OXM) and develop a resistant analog (prOXM).

Main Methods:

• Utilized mass spectrometry to identify the serum cleavage site of oxyntomodulin (OXM).
• Employed data-driven synthesis to create a proteolysis-resistant OXM analog (prOXM).
• Assessed prOXM activity in binding, insulin secretion, and in vivo glucose regulation assays.

Main Results:

• Identified the serum cleavage site of OXM.
• Synthesized prOXM, a proteolysis-resistant analog with similar binding and insulin secretion activity to OXM.
• Demonstrated that prOXM effectively reduces basal glucose levels and improves glucose tolerance in mice.

Conclusions:

• The data-driven synthesis strategy is effective for creating proteolysis-resistant peptide hormone analogs.
• prOXM shows therapeutic potential for managing glucose levels.
• This approach can be applied to develop resistant analogs for other peptide hormones, expanding therapeutic options.