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Lessons from Amide-to-Alkene Peptidomimetics

Developing robust peptide bond isosteres to replace the hydrolyzable peptide bond poses a significant challenge across the fields of organic chemistry, medicinal chemistry, and chemical biology. Peptides and proteins, which utilize peptide bonds as their backbones, play pivotal roles in numerous biological processes, prompting the exploration of stable yet functionally similar substitutes. This seminar will focus on our research into fluoroalkene and chloroalkene dipeptide isosteres (FADIs and CADIs), highlighting the design strategies and synthetic methodologies we developed. Fluoroalkene dipeptide isosteres (FADIs) have been thought of as one of the most ideal isosteres to mimic the shape and function of the ground state of the peptide bond, as extensively documented in the literature. In contrast, chloroalkene dipeptide isosteres (CADIs) possessing the chlorine atom as the carbonyl oxygen equivalent have garnered less attention, albeit with the advantages of the chlorine substituent as a bioisostere for many functional groups. We will present our latest findings on incorporating CADIs into peptides, specifically within b-turn and b-sheet structures, to enhance their biological activity and stability. The discussion will extend to the practical applications of (Z)-CADIs in creating bioactive peptides, highlighting their potential to advance the development of peptidomimetic drugs.