Solid phase synthesis of peptide-selenoesters.

Area of Science:

• Biochemistry
• Organic Chemistry
• Synthetic Chemistry

Background:

• Native chemical ligation (NCL) is crucial for synthesizing complex proteins.
• Traditional NCL relies on peptide-thioesters, which can limit reaction rates and applicability.
• Developing faster and more versatile ligation strategies is essential for advancing protein chemistry.

Purpose of the Study:

• To introduce peptide selenoesters as a more reactive alternative to peptide-thioesters in NCL.
• To develop a general and straightforward method for synthesizing peptide selenoesters.
• To evaluate the stability and reactivity of peptide selenoesters under NCL conditions.

Main Methods:

• Peptide selenoesters were synthesized using a novel, general procedure involving a functionalized resin.
• The stability of peptide selenoesters was assessed under various conditions, including hydrolysis and aminolysis.
• Reactivity and ligation rates of selenoesters were compared to thioesters under native chemical ligation conditions.

Main Results:

• Peptide selenoesters significantly accelerate ligation rates compared to thioesters.
• A new, simple, and cost-effective method for producing high-quality peptide selenoesters was established.
• Selenoesters exhibit slightly higher reactivity and susceptibility to hydrolysis/aminolysis but are stable at pH 6.5.
• Rapid selenoester-mediated ligation is favored under mildly acidic conditions.

Conclusions:

• Peptide selenoesters offer a powerful advancement for native chemical ligation, enabling faster couplings and new strategies.
• The developed synthesis procedure facilitates routine production of high-quality peptide selenoesters.
• Selenoesters provide a stable and efficient alternative to thioesters for complex protein synthesis, particularly under mildly acidic conditions.