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Related Experiment Video

Updated: Sep 15, 2025

Quantification of Hypopigmentation Activity In Vitro
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Endogenous tyrosinase-catalyzed therapeutics.

Yawen You1,2,3, Zhaochen Guo4, Yixin Wang1,2,3

  • 1Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.

Nature Communications
|July 12, 2025
PubMed
Summary

This study introduces a novel tyrosinase (TYR)-based platform for intracellular drug generation. This approach effectively treats hyperpigmentation and melanoma by degrading TYR protein and overcoming drug resistance.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Medicinal Chemistry
  • Dermatology

Background:

  • Tyrosinase (TYR) is crucial for melanin synthesis, making it a therapeutic target for melanin-associated skin disorders.
  • Abnormal melanin levels are linked to severe skin diseases, necessitating innovative treatment strategies.
  • Existing therapies face challenges like drug resistance and targeted delivery.

Purpose of the Study:

  • To develop a tyrosinase-based in situ catalytic platform for intracellular drug generation.
  • To create TYR-catalyzed therapeutics for hyperpigmentation and melanoma treatment.
  • To leverage endogenous copper-catalyzed azide-alkyne cycloaddition (CuAAC) for drug synthesis.

Main Methods:

  • Mechanistic validation of TYR catalytic activity using ab initio molecular dynamics (AIMD) and experimental catalysis.
  • Development of TYR-catalyzed in-situ formed proteolysis-targeting chimeras (PROTACs) to degrade intracellular TYR.
  • Design of a TYR-catalyzed in-situ activated prodrug strategy to combat drug resistance.

Main Results:

  • The TYR-catalyzed therapeutics efficiently alleviated skin hyperpigmentation in male mouse models within 48 hours.
  • The platform successfully resensitized drug-resistant melanoma cells to chemotherapeutics, controlling tumor growth.
  • AIMD and experimental data confirmed the potent catalytic activity of TYR.

Conclusions:

  • An integrative platform leveraging endogenous TYR catalytic activity for therapeutic generation via in situ bioorthogonal chemistry was established.
  • This approach offers a promising strategy for treating melanin-associated skin diseases, including hyperpigmentation and melanoma.
  • The study demonstrates the potential of TYR-catalyzed intracellular drug generation for enhanced therapeutic outcomes.