Metacaspases are enzymes involved in programmed cell death pathways in plants, fungi, protozoa, bacteria and algae. These enzymes are absent in humans and differ significantly from orthologous human caspases. Therefore, metacaspase inhibitors have therapeutic potential. Here we report the novel synthesis of a library of possible Schizophyllum commune metacaspase inhibitors. Maya Berg developed potent heteroarylketone metacaspase inhibitors for T. brucei metacaspase-2 composed of a Cbz-protected arginine-benzothiazole derivative; our library of potential S. commune metacaspase inhibitors is based on this motif. Krystyna Demkiw developed a robust and direct method of synthesizing heteroaryl ketones directly from carboxylic acids and heteroaryl halides. We have extended the scope of Demkiw’s method to include protected amino acid derivatives and demonstrated the stereospecificity of this approach. We will report on the progress and difficulties synthesizing peptidomimetic molecules using chemistry inspired by Demkiw’s method. Progress toward inhibition and binding assays for the compounds will be discussed. Characterizing a potent inhibitor-enzyme complex will further our understanding of the active site and other areas for potential intervention.
