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OICR-41103作为DCAF1 WD40域的化学探针使用

Serah W Kimani¹, Mahmoud Noureldin^2,3, Brian Wilson²

¹Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.

Communications biology

|July 19, 2025

概括

我们开发了OICR-41103,一种针对人类DCAF1 (DDB1和CUL4相关因子1) 的化学探针. 这种探测器通过阻断病毒蛋白相互作用,显示出开发新的癌症和艾滋病治疗的潜力.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

人类DCAF1 (DDB1和CUL4相关因子1) 对蛋白质稳态和向蛋白质降解至关重要.
DCAF1的WDR域为E3泛素酶招募基质,影响细胞增殖和瘤发生.
病毒蛋白利用DCAF1降低宿主抗病毒因子,呈现治疗点.

研究的目的:

为DCAF1 WDR域开发一种强效,选择性和细胞活性化学探针.
在瘤学和抗病毒策略中研究DCAF1向化合物的治疗潜力.
探索DCAF1作为向蛋白质降解和HIV治疗的目标.

主要方法:

开发OICR-41103,一种新型的小分子探测器,由OICR-8268.8衍生出来.
对DCAF1-OICR-41103复合物的共同晶体结构的确定.
生物化学和细胞测试,以评估从DCAF1.1的Vpr蛋白位移.

主要成果:

OICR-41103是一种强效,选择性和细胞活性化学探针,用于DCAF1.1.
共同晶体结构阐明了OICR-41103在DCAF1 WDR中央口袋中的结合.
在体外和细胞内,OICR-41103有效地从DCAF1中取代了lentiviral Vpr蛋白.

结论:

OICR-41103是一种有价值的化学探针,用于研究DCAF1的功能.
探测器的结构和活动支持其对PROTAC开发的潜力.
通过破坏病毒与宿主相互作用,OICR-41103展示了开发新型HIV治疗方法的前景.

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