Clickable tryptophan modification for late-stage diversification of native peptides

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biochemistry

Background:

• Tryptophan (Trp) is crucial for peptide drug-target interactions.
• Modifying Trp residues offers a route to diversify peptide drugs.
• Existing methods often lack broad applicability or require harsh conditions.

Purpose of the Study:

• To develop a novel, catalyst-free method for tryptophan modification.
• To enable late-stage diversification of native peptides.
• To improve the pharmacokinetic properties of therapeutic peptides.

Main Methods:

• Catalyst-free C2-sulfenylation of tryptophan using 8-quinoline thiosulfonate reagents.
• Reaction conducted in trifluoroacetic acid (TFA) for broad peptide solubility.
• Incorporation of various sulfur-containing groups (e.g., SCF3, SCF2H).

Main Results:

• Successful modification of tryptophan in diverse peptide sequences.
• Demonstrated compatibility with all 20 proteinogenic amino acids.
• Late-stage modification of 15 therapeutic peptides (1.0–7.6 kDa).
• Improved bioactivity and serum stability in modified melittin analogs.

Conclusions:

• The developed method provides a versatile tool for peptide drug diversification.
• Trp modification via C2-sulfenylation enhances peptide pharmacokinetic properties.
• This approach holds potential for developing next-generation peptide therapeutics.