Small molecule modifiers of circadian clocks

Abstract

Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research.

Fig. 1

Small molecule modifiers of circadian clocks. In the mammalian circadian clock system, external signals are transmitted via input pathways to the molecular oscillator consisted of interlocked feedback loops. The molecular oscillator in turn orchestrates output functions which may reciprocally regulate the clock via feedback regulation. Small molecule modifiers of the clocks may target the input pathways, the core clock, or output pathways with feedback regulatory functions

Fig. 2

Stimulatory effects of clock-enhancing small molecules (CEMs) on reporter rhythms in homozygous Clock∆19/Clock∆19 (a) and Bmal1 −/− (b) fibroblast cells. Luminescence recording was carried out as previously described [81]. Compared with the Per2::luc reporter, Per2::lucSV contains an exogenous SV40 polyA element which increases reporter luminescence [81]. The X- and Y-axes indicates time and luminescence, respectively. In (b) right panel, daily dosing times of CEM1 are indicated by the arrowheads corresponding to the spikes in bioluminescence recordings