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Regulation of the circadian clock is essential to sleep and health and involves a core set of clock genes that regulate large gene transcription networks. Here, Ju et al. identify the adenosine analogue cordycepin as a circadian phase shifter. Cordycepin targeted RuvB-like ATPase 2 to disrupt its interaction with the core clock component BMAL1, and caused disassembly of a circadian regulatory super-complex which enabled transcription of E-box containing clock genes. Cordycepin induced a rapid 12 hour clock phase shift in human cells, mouse tissues and mice. In a mouse jet-lag model, cordycepin penetrated the BBB and accelerated recovery.