Science：KL001是一种与生物钟失调有关的小分子

7月12日，Science在线报道了一种新颖，有效的研究生物节律的小分子物质KL001.

生物钟失调一直伴随着许多生理障碍，包括代谢性疾病。虽然调节生物钟功能的小分子可能提供对这类疾病的治疗方法，但已被发现的化合物只有少数选择性靶向调节关键生物钟蛋白质。

通过一个非偏性以细胞为基础的昼夜节律筛选，研究者确定一个称为KL001的小分子，可特异性地与昼夜节律关键调节因子--蓝光受体蛋白cryptochrome(CRY)相互作用。 KL001阻止泛素依赖的CRY降解，导致昼夜节律期延长。

将KL001与数学模型相结合，研究者发现CRY1和CRY2在节律周期调节具有相似的功能。此外，KL001介导的CRY稳定性可抑制在原代肝细胞中，胰高血糖素诱导的糖异生。 由此，KL001为CRY依赖的生理过程提供了一个研究工具，同时可促进研发基于生物节律的糖尿病治疗法。

doi:10.1016/j.cell.2011.10.017
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Identification of Small Molecule Activators of Cryptochrome

Tsuyoshi Hirota1,7,Jae Wook Lee2,Peter C. St. John3,Mariko Sawa1,Keiko Iwaisako4,Takako Noguchi5,Pagkapol Y. Pongsawakul1,Tim Sonntag1,David K. Welsh5,6,David A. Brenner4,Francis J. Doyle III3,Peter G. Schultz2,*,Steve A. Kay

Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compounds have been identified that selectively target core clock proteins. From an unbiased cell-based circadian screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.