Peptides are a promising class of drugs that may have a large therapeutic window due to their high selectivity and low toxicity. However, despite promising in vitro data for many peptide drug candidates, relatively few peptide therapeutics have reached market due to in vivo challenges. Most significantly, peptides are rapidly cleaved by protease enzymes. We have previously demonstrated that incorporating α,β-dehydroamino acids (ΔAAs) into the backbone of 310 helical peptides significantly reduces the vulnerability of peptides to proteases. We hypothesize based on our results that incorporating larger, cyclic ΔAAs into this structure will further increase proteolytic resistance. In addition, NMR data provides evidence that peptides containing ΔAAs favor more rigid and tightly folded states. Data from recent experiments that support our hypothesis will be presented.

Impact of cyclic dehydroamino acids on the structure of 310 helical peptides

ACS Spring 2022

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