A catalyst selection protocol that identifies biomimetic motifs from β-hairpin libraries

Area of Science:

• Biochemistry
• Organic Chemistry
• Catalysis

Background:

• Enzyme active sites utilize histidine residues to catalyze crucial biochemical reactions.
• Mimicking enzyme catalytic strategies in synthetic systems is a key challenge in chemistry.

Purpose of the Study:

• To develop a method for selecting peptide catalysts that replicate histidine-based enzyme catalysis.
• To identify catalysts that accelerate acyl- and phosphonyl-transfer reactions in organic solvents.

Main Methods:

• Solid-phase synthesis of a peptide library containing histidine residues.
• Application of a reactive tagging scheme for selection in organic solvents.
• Kinetic analysis to determine catalytic efficiency (krel).

Main Results:

• Successful selection of histidine-containing β-hairpin peptides with catalytic activity.
• Achieved rate accelerations (krel) of up to 2.4 × 10^8 in organic solvents.
• Demonstrated that selected catalysts reproduce His-based enzyme active site strategies.

Conclusions:

• Solid-phase selection coupled with reactive tagging is effective for discovering peptide catalysts.
• Histidine-containing peptides can be engineered to efficiently catalyze acyl- and phosphonyl-transfer reactions in non-aqueous environments.
• This approach offers a route to artificial enzymes for organic synthesis.