Targeting a diseased cell population over a healthy cell population in drug discovery still remains a challenge. Prodrugs have been effective in targeted drug release to improve a parent drug’s off-target effects and pharmacokinetic profile. We are interested in developing hybrid molecules that contain an unnatural peptide sequence linked to a biologically active molecule. The peptide sequence has been designed to interact with the immunoproteasome (iCP). The iCP is an isoform of the proteasome that is overly expressed when a cell is infected or introduced to inflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. Once the hybrid molecule binds to the chymotrypsin-like active site of the iCP, the biologically-relevant molecule will be released from the peptide. Our initial results indicate this approach can release a number of cytotoxic molecules mainly in the cells expressing the iCP. The sequence of the peptide can also be modified depending on the desire to also inhibit excessive iCP function. Further medicinal chemistry optimization and biochemical characterization has further allowed us to better understand what functional groups are favored by the iCP’s substrate channel for more efficient cleavage and therefore, activation of our prodrug-like scaffold.

Bifunctional molecules as prodrugs for the immunoproteasome

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ACS Fall 2022

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