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对BMAL1进行药物靶向调节可调控昼夜节律和免疫途径。

Pharmacological targeting of BMAL1 modulates circadian and immune pathways.

作者信息

Pu Hua, Bailey Laura C, Bauer Ludwig G, Voronkov Maria, Baxter Matthew, Huber Kilian V M, Khorasanizadeh Sepideh, Ray David, Rastinejad Fraydoon

机构信息

Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.

Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

出版信息

Nat Chem Biol. 2025 May;21(5):736-745. doi: 10.1038/s41589-025-01863-x. Epub 2025 Mar 25.

DOI:10.1038/s41589-025-01863-x
PMID:40133642
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12037410/
Abstract

The basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) proteins BMAL1 and CLOCK heterodimerize to form the master transcription factor governing rhythmic gene expression. Owing to connections between circadian regulation and numerous physiological pathways, targeting the BMAL1-CLOCK complex pharmacologically is an attractive entry point for intervening in circadian-related processes. In this study, we developed a small molecule, Core Circadian Modulator (CCM), that targets the cavity in the PASB domain of BMAL1, causing it to expand, leading to conformational changes in the PASB domain and altering the functions of BMAL1 as a transcription factor. Biochemical, structural and cellular investigations validate the high level of selectivity of CCM in engaging BMAL1, enabling direct access to BMAL1-CLOCK cellular activities. CCM induces dose-dependent alterations in PER2-Luc oscillations and orchestrates the downregulation of inflammatory and phagocytic pathways in macrophages. These findings collectively reveal that the BMAL1 protein architecture is inherently configured to enable the binding of chemical ligands for functional modulation.

摘要

基本螺旋-环-螺旋PER-ARNT-SIM（bHLH-PAS）蛋白BMAL1和CLOCK形成异二聚体，构成调控节律性基因表达的主要转录因子。由于昼夜节律调节与众多生理途径之间存在联系，从药理学角度靶向BMAL1-CLOCK复合物是干预昼夜节律相关过程的一个有吸引力的切入点。在本研究中，我们开发了一种小分子核心昼夜节律调节剂（CCM），它靶向BMAL1的PASB结构域中的腔，使其扩张，导致PASB结构域发生构象变化，并改变BMAL1作为转录因子的功能。生化、结构和细胞研究证实了CCM与BMAL1结合具有高度选择性，能够直接影响BMAL1-CLOCK的细胞活性。CCM诱导PER2-Luc振荡的剂量依赖性变化，并协调巨噬细胞中炎症和吞噬途径的下调。这些发现共同揭示，BMAL1的蛋白质结构天生就能够结合化学配体以进行功能调节。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a98/12037410/8104866c0f89/41589_2025_1863_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a98/12037410/bbe8dbcf2db9/41589_2025_1863_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a98/12037410/5a3de19ef8eb/41589_2025_1863_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a98/12037410/a62d2da368de/41589_2025_1863_Fig10_ESM.jpg
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