Abstract
Inhibitors of the enzyme tyrosinase have found clinical utility as agents to treat disorders of hyperpigmentation of the skin. Potential cellular toxicity and carcinogenicity of currently available tyrosinase inhibitors motivates finding safer and more effective alternatives. “Repurposed” drugs have recently attracted attention due to the possibility of finding safe and effective medical treatments with less time spent in early stage drug development. We report the identification and characterization of potent tyrosinase inhibitors that are “repurposed” existing drugs. Para-acetaminophenols, exemplified by the anti-inflammatory agent acetaminophen, displayed inhibitory activity against mushroom tyrosinase. Detailed analysis of enzyme kinetics in the presence of acetaminophen showed that it acts as a noncompetitive inhibitor. Further, acetaminophen behaved as an alternative substrate of the enzyme. Substituted analogs of acetaminophen were also effective inhibitors, but behaved as competitive inhibitors. Another class of approved drugs that inhibited the enzyme were found to display very potent inhibition of tyrosinase, with a Ki of 900 nanomolar. Kinetic analysis revealed this class of molecules acted as competitive inhibitors, with no evidence of undergoing chemical transformation by tyrosinase or enzyme inactivation. This class of molecules likely inhibits tyrosinase by coordinating with a copper ion in the enzyme active site. This type of strong and specific interaction with tyrosinase may make drugs of this class clinically useful as skin whitening agents.
Published Version
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