Robust synthesis of an array of amino acid-derived heteroaryl ketones as potential inhibitors for metacaspases found in S. commune

Metacaspases belong to a family of cysteine-dependent proteases found in protozoa, fungi, and plants and are instrumental in a multitude of cellular processes including programmed cell death. Though structurally similar to their mammalian equivalent - caspases, metacaspases demonstrate a distinctive substrate specificity. Berg identified a potent inhibitor for a metacaspase found in T. brucei based on a peptidomimetic heteroaryl ketone scaffold, an arginine-derived benzothiazolyl ketone. Demkiw generated aromatic heteroaryl ketones using a one-pot Grignard-aided chelation of aromatic carboxylic acids. Our work aims to extend Demkiw's approach using peptidomimetic aliphatic acids to synthesize potential metacaspase inhibitors for S. commune. Our presentation discusses this approach generally and reports the stereospecificity of various amino acid derivatives. Future research aims to assess the inhibition of S. commune metacaspases with various peptidomimetic heteroaryl ketones.