Galactose-modified small molecule modulator targets RORα to enhance circadian rhythm and alleviate periodontitis-associated alveolar bone loss

Abstract

Circadian rhythm disorders are associated with dysfunction in inflammatory diseases, and targeted regulation of the circadian rhythm could serve as an intervention strategy. RORα/γ, as core components of circadian clock genes, positively modulate the key circadian molecule BMAL1. In this study, Gala-SR, a potent small-molecule compound designed to effectively regulate circadian rhythms, was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078, an unique synthetic agonist of RORα/γ. Compared with SR1078, Gala-SR exhibited significantly greater aqueous solubility, cytocompatibility, pharmacokinetic characteristics and efficacy in the targeted activation of RORα. Importantly, Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo. In circadian rhythm disordered mice with periodontitis, Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner, and alleviated alveolar bone loss. Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm. This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.

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Funding

National Key R&D Program of China (2021YFC2400400/04)

National Natural Science Foundation of China (National Science Foundation of China)(82271036)

Young Elite Scientist Sponsorship Program by cst(2022QNRC001).

National Natural Science Foundation of China for Distinguished Young Scholars (22025102)

RIGHTS & PERMISSIONS

The Author(s)