Wednesday, May 22, 2024 - 4:00pm

Abstract: While the use of small organic molecules as therapeutic agents (drugs) goes back to antiquity, the therapeutic use of peptide drugs is a very recent phenomenon. Approximately 60 peptides have been introduced for clinical use in the past 25 years. 85% of these peptides contain at least one non-proteinogenic amino acid—those outside of the naturally encoded and translated amino acids—to confer metabolic stability, receptor potency and/or receptor selectivity to the peptide. Finding the optimal residue involves trial and error, each variant peptide being made as the unique product of a long, tedious, and chemically inefficient Solid Phase Peptide Synthesis (SPPS) procedure. We introduce a radically new approach to greatly accelerate the discovery process. Our approach takes advantage of a naturally encoded ‘pro-amino acid’, dehydroalanine, as a chemical lynchpin. Implanted into ordinary peptides, dehydroalanine can become one of any number of non-proteinogenic residues by reaction with one- or two- electron nucleophiles. Applied in parallel formats, entirely new libraires of peptides that address new therapeutic targets can be made, purified, quantified, and biochemically tested.


Steven Bloom


University of Kansas


RH 104