The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101 and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioural rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.

中文翻译：

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隐花色素调节化合物对斑马鱼昼夜节律的影响

生物钟控制着各种生理过程的日常节律，其功能受损会导致包括睡眠障碍在内的许多疾病。调节时钟功能的化合物有望用于治疗与生物钟相关的疾病。我们之前发现了小分子化合物 KL001、KL101 和 TH301，它们通过直接靶向哺乳动物中的时钟蛋白隐花色素 (CRY) 来延长细胞生物钟的周期。KL001 靶向 CRY1 和 CRY2 异构体，而 KL101 和 TH301 是异构体选择性化合物，需要 CRY C 末端区域才能发挥作用。为了进一步应用这些化合物，需要研究对有机体水平运动活动节律的影响。在这里，我们使用斑马鱼幼虫作为体内模型系统，发现 KL001 以剂量依赖性方式延长了运动活动节律的周期。相比之下，KL101 和 TH301 对周期没有影响。CRY C 末端区域的氨基酸序列在斑马鱼和哺乳动物中是不同的，支持该区域对 KL101 和 TH301 影响的重要性。该研究证明了 CRY 调节对控制生物体昼夜行为节律的功效，并表明同种型选择性 CRY 调节化合物的作用存在物种依赖性差异。支持该区域对 KL101 和 TH301 影响的重要性。该研究证明了 CRY 调节对控制生物体昼夜行为节律的功效，并表明同种型选择性 CRY 调节化合物的作用存在物种依赖性差异。支持该区域对 KL101 和 TH301 影响的重要性。该研究证明了 CRY 调节对控制生物体昼夜行为节律的功效，并表明同种型选择性 CRY 调节化合物的作用存在物种依赖性差异。