Peptides are now being recognized as valuable therapeutic agents with the potential to address unmet medical needs. Their ability to target complex biological processes with greater precision compared to small-molecule drugs, coupled with their relative simplicity and cost-effectiveness compared to large biological drugs like antibodies, makes them a promising area of research. There are currently over 100 FDA-approved peptide drugs on the market, with around 40 of them containing at least one tryptophan (Trp) residue, a crucial amino acid. Modifying these Trp residues within peptide molecules can have a significant impact on drug-target interactions, as well as improving properties such as drug stability, bioavailability, and pharmacokinetics.
The Challenges of Peptide Modification
However, making modifications to these functionally dense molecules poses several challenges. Peptides have nucleophilic functionalities that make them sensitive to redox conditions, complicating the modification process. Additionally, the limited solvents available for dissolving unprotected peptides further complicates the situation. As a result, developing site-specific late-stage peptide modifications can be a daunting task for researchers.
Recently, a team led by Professor Xuechen LI from the Department of Chemistry of The University of Hong Kong (HKU) developed a groundbreaking clickable tryptophan modification strategy. This innovative approach allows for the easy modification of specific parts of a peptide molecule, even at the late stages of drug development. By leveraging a catalyst-free C2-sulfenylation reaction using S-modified quinoline-containing thiosulfonate reagents, the researchers were able to efficiently introduce a variety of functional groups onto Trp residues within native peptide structures. These groups included trifluoromethylthio, difluoromethylthio, (ethoxycarbonyl) difluoromethylthio, alkylthio, and arylthiol.
This method was successfully applied to the late-stage modification of several FDA-approved peptide drugs, demonstrating its versatility and applicability in the modification of peptide-based active pharmaceutical ingredients. The team found that the bioactivity and serum stability of modified melittin analogs were significantly improved, showcasing the potential of this method in drug development. Furthermore, the method’s effectiveness in modifying natural products like darobactin and chloropeptin I, as well as drug leads from phage display and mRNA display, highlights its broader utility in the field.
The team believes that this single-step clickable late-stage Trp modification method will become a valuable tool for medicinal chemists, peptide chemists, and chemical biologists. With the ability to easily generate structural analogs in a cost-efficient manner, this strategy could play a crucial role in optimizing drug activities and pharmacokinetic properties in the future. Its potential to create molecular libraries and functional probes for natural product late-stage diversification further underscores its value in advancing peptide drug development.
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