小眼畸形相关转录因子
酪氨酸酶
熊果苷
化学
斑马鱼
蛋白质水解
皮肤美白
泛素
生物化学
药物发现
配体(生物化学)
计算生物学
细胞生物学
药理学
酶
受体
生物
活性成分
基因
作者
Meng Xu,Ziqing Zhang,Peixi Zhang,Qiaolai Wang,Yuanxi Xia,Chenlei Lian,Jia Liu,Jie‐Qing Liu
标识
DOI:10.1016/j.bmc.2023.117537
摘要
Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a promising approach for targeted protein degradation. In this study, we focused on tyrosinase (TYR), a key enzyme involved in melanin synthesis and pigmentation. For this target, we designed and synthesized a series of PROTACs (D3-D9), employing Rhein as the target protein-ligand. Through some experimental tests, we made a significant discovery. Preliminary experimental results show that the most promising compound (D6) demonstrated the ability to degrade MITF and inhibit the expression and TYR in B16-F10 cells, effectively suppressing melanogenesis in zebrafish. Notably, at equivalent concentrations, the whitening effect of D6 surpassed that of its precursor Rhein and was even comparable to that of the well-established whitening agent, β-arbutin. Validating experiments further revealed that the action of D6 was reliant on the E3 ligand, indicating its capacity to degrade TYR and MITF through the ubiquitination pathway. Whether D6 acts directly on TYR or MITF needs to be further explored. These compelling results underscore the tremendous whitening potential of D6, suggesting its suitability as a valuable lead for whitening agents and its potential to expand the range of whitening cosmetic products.
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