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Axin, the classic scaffold protein of Wnt/β-catenin signalling as a potential drug-target for vitiligo
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  • Duozhi Chen,
  • Shirui Fan,
  • Xueying Lu,
  • Chenxu Jing,
  • Deng Zang,
  • Bijuan Yang,
  • Jieyun Cai,
  • Yiting Wang,
  • Xinfang Zhang,
  • Lin Li,
  • Haji Akber Aisa,
  • Xiaojiang Hao
Duozhi Chen
Kunming Institute of Botany Chinese Academy of Sciences
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Shirui Fan
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences
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Xueying Lu
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences
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Chenxu Jing
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences
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Deng Zang
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences
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Bijuan Yang
Kunming Institute of Botany Chinese Academy of Sciences
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Jieyun Cai
Kunming Institute of Botany Chinese Academy of Sciences
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Yiting Wang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences
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Xinfang Zhang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences
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Lin Li
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
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Haji Akber Aisa
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences
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Xiaojiang Hao
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences
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Abstract

Background and Purpose: Humans have been fighting vitiligo for centuries but still being inferior due to the lack of efficiency drugs and therapies. While some research has implied the therapeutic potential of Wnt/β-catenin signalling on curing vitiligo but correlation mechanism is not clear and no Wnt-specific anti-vitiligo drug has been reported. Here, We identified how vitiligo could be treated by regulating Wnt and two lead compounds of new anti-vitiligo drugs have been found. Experimental Approach: Wnt agonists were rational synthesized and then be evaluated their effects on vitiligo in B16 cells and C57B/L mouse. Furthermore, Co-IP and Site-directed mutagenesis were employed to indicate the mechanism and the target of the compounds. Key Results: HCJA121 and HCJA404 could significantly promote the synthesis of melanin, restore the pigmented function of skin, and improve the symptoms of vitiligo. Mechanism studies indicated that HCJA121 and HCJA404 target the DAX domain of Axin by binding to LYS781 and LEU784 then potentiate the Axin-LRP6 association and eventually promoted melanogenesis. Conclusions and Implications: These findings imply an alternative regulatory mechanism of melanogenesis and the Axin protein could be a new target for anti-vitiligo agents which reveal a therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may represent potential compounds for vitiligo treatment.

Peer review status:UNDER REVIEW

18 Nov 2020Submitted to British Journal of Pharmacology
19 Nov 2020Assigned to Editor
19 Nov 2020Submission Checks Completed
10 Dec 2020Reviewer(s) Assigned