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Review
. 2020 Dec;35(1):1267-1286.
doi: 10.1080/14756366.2020.1772249.

Recent advances in modulators of circadian rhythms: an update and perspective

Shenzhen Huang  1 , Xinwei Jiao  1 , Dingli Lu  1 , Xiaoting Pei  1 , Di Qi  1 , Zhijie Li  1
Affiliations
Free PMC article
Review

Recent advances in modulators of circadian rhythms: an update and perspective

Shenzhen Huang et al. J Enzyme Inhib Med Chem. 2020 Dec.
Free PMC article

Abstract

Circadian rhythm is a universal life phenomenon that plays an important role in maintaining the multiple physiological functions and regulating the adaptability to internal and external environments of flora and fauna. Circadian alignment in humans has the greatest effect on human health, and circadian misalignment is closely associated with increased risk for metabolic syndrome, cardiovascular diseases, neurological diseases, immune diseases, cancer, sleep disorders, and ophthalmic diseases. The recent description of clock proteins and related post-modification targets was involved in several diseases, and numerous lines of evidence are emerging that small molecule modulators of circadian rhythms can be used to rectify circadian disorder. Herein, we attempt to update the disclosures about the modulators targeting core clock proteins and related post-modification targets, as well as the relationship between circadian rhythm disorders and human health as well as the therapeutic role and prospect of these small molecule modulators in circadian rhythm related disease.

Keywords: Circadian rhythm; circadian rhythm-related disease; clock proteins; post-modification targets; small-molecule modulators.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
The physiological basis for the generation and maintenance of mammalian circadian rhythm. Reproduced from Chen et al.
Figure 2.
Figure 2.
Molecular clock loops and their potential targets with representative small molecule modulators. CLOCK: circadian locomotor output cycles kaput; BMAL1: brain and muscle ARNT-like 1; CRY: cryptochrome; PER: period; ROR: RAR-related orphan receptor; RRE: retinoic acid receptor-related orphan receptor binding element; CCGs: clock-controlled genes; CK1: casein kinase 1; CDKs: cyclin-dependent kinases; GSK3β: glycogen synthase kinase 3β; SIRT1: silent information regulator 1; PPARγ: peroxisome proliferator-activated receptor γ; DNA TOPs: DNA topoisomerases. Reproduced from He and Chen. Copyright 2016 American Chemical Society.
Figure 3.
Figure 3.
The structure of modulators targeting CRYs.
Figure 4.
Figure 4.
Development and structure of modulators targeting REV-ERBs.
Figure 5.
Figure 5.
Natural structure of modulators targeting RORs.
Figure 6.
Figure 6.
Development and structure of synthetic modulators targeting RORs.
Figure 7.
Figure 7.
Development and structure of synthetic modulators targeting kinases.
Figure 7.
Figure 7.
Development and structure of synthetic modulators targeting kinases.
Figure 8.
Figure 8.
Development and structure of synthetic modulators targeting epigenetic proteins and others.
Figure 9.
Figure 9.
Implications in circadian rhythm-related diseases.
See this image and copyright information in PMC

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Grants and funding

This research was supported by the National Natural Science Foundation of China [grant number 81770962 to ZL], [grant number 81470603 to ZL]; Technology of the Peoplés Republic of China [grant number 2018YFC0114500 to ZL]; and Doctoral Research and Development Foundation of Henan Provincial People’s Hospital [grant number ZC20190146 to SH].

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