Making Your Own Enemies: Suicide Inhibition of Hemoproteins

Hemoproteins play pivotal roles in biological systems, such as transporting oxygen (through hemoglobin and myoglobin) and detoxifying foreign substances via metabolic enzymes (cytochrome P450). However, hemoproteins have also become significant targets for therapeutic intervention due to two critical factors: (i) an imbalance of heme observed in various cancers and (ii) the reliance of many pathogens, including fungi and bacteria, on hemoproteins for their survival. Hence, heme and hemoproteins can serve as promising targets for innovative therapeutic strategies. A novel mode of action is proposed employing the concept of a Trojan horse: the initial compound does not display biological activity, but is rather activated upon interaction with the therapeutic target to ultimately block it. In particular, this will be realized employing functional groups that get modified by the iron atoms in hemoproteins to ultimately result in irreversible chemical bonding. This leads to inhibition of the initial biological function the target protein commits suicide. The strategy employs structures previously used mainly as tool compounds in research or diagnostics based on recent reports on an interesting chemical behavior upon contact with heme-iron. This serves as starting point towards the generation of new structures as mechanism-based suicide drug candidates. Upon successful development of selective interactions with target proteins, this represents a novel and innovative strategy for hemoprotein inhibition, opening the door for new treatments for cancer and infectious diseases.