Pharmacological Interventions to Circadian Clocks and Their Molecular Bases. Issue 12 (29th May 2020)

• Record Type: Journal Article
• Authors: Miller, Simon; Hirota, Tsuyoshi
• Is Part Of: Journal of molecular biology. Volume 432:Issue 12(2020)
• Page Start: 3498
• Page End: 3514
• Publication Date: 2020-05-29
• Subjects: Circadian clock -- Clock proteins -- Clock-related diseases -- Protein kinases -- Small-molecule compounds; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.01.003
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Daily physiological rhythms are regulated by the body's internal timekeeper known as the circadian clock. Expression, post-translational modification, and degradation of clock proteins constituting the circadian clock are precisely controlled in a rhythmic manner. Perturbation of these processes by nature and nurture results in physiological dysfunction and diseases. Small-molecule modulators of clock or clock-related proteins can adjust clock functions, and thus represent a promising method of therapeutic treatment for a range of clock-related diseases. In this review, we will introduce the identification and development of small-molecule compounds that target clock proteins, as well as X-ray crystal structures of protein-compound complexes that facilitate the understanding of clock protein regulation and drug derivatization. Furthermore, we describe the effects of these compounds in a diseased setting and discuss the therapeutic potential of clock modulators. Graphical abstract: Image 1 Highlights: Clock proteins are regulated posttranslationally by protein kinases. Target-based and phenotypic screening identified clock-modulating compounds. Clock-modulating compounds regulate protein kinases and clock proteins. Crystallographic studies facilitate understanding of clock-modulating compounds. Clock-modulating compounds have therapeutic potential in a host of diseases.