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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Guangxia Feng,
  • Zhiwen Liao,
  • Yifan Wang,
  • Qingming Tang,
  • Nayun Li,
  • Cheng Li,
  • Yuqing Liu,
  • Renlong Liu,
  • Mingjian Cui,
  • Wenjie Fan,
  • Ying Yin,
  • Lingkui Meng,
  • Jing Zeng,
  • Zetao Chen,
  • Guanzheng Luo,
  • Peng Xiang,
  • Qian Wan,
  • Lili Chen

摘要

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.