生物科技研究所邱于芯助理教授Assistant Professor Yu-Hsin Chiu, Institute of Biotechnology
生命科學暨醫學院教師傑出研究介紹
Introduction to Outstanding Research by Faculty Members of the College of Life Sciences and Medicine
生物科技研究所 邱于芯助理教授
Assistant Professor Yu-Hsin Chiu, Institute of Biotechnology
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清大生醫學院生技所邱于芯助理教授與研究團隊成員 Assistant Professor Yu-Hsin Chiu of the Institute of Biotechnology, College of Life Sciences and Medicine, National Tsing Hua University, with research team member |
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Novel Naphthyridones Targeting Pannexin 1 for Colitis Management |
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先進科學Advanced Science |
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主持人Principle Investigator： 邱于芯 助理教授 Yu-Hsin Chiu, Assistant Professor 國立清華大學生命科學暨醫學院 生物科技研究所 Institute of Biotechnology (IBT), College of Life Science and Medicine (CLSM), National Tsing Hua University (NTHU). 參與者Participants:： 謝興邦 特聘研究員兼所長 國家衛生研究院 Hsing-Pang Hsieh, Distinguished Investigator and Director, National Health and Research Institutes (NHRI) |
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摘要 Abstract |
Pannexin 1 (PANX1)是大孔徑離子通道，在細胞凋亡與嘌呤訊號中扮演關鍵角色。因現有抑制劑選擇性差，本研究專案開發出新型高專一性萘啶酮衍生物，有效抑制PANX1且無脫靶問題，並闡明其分子作用機制與結合位點。藉由DSS誘導小鼠結腸炎模式，證實此抑制劑可減緩腸道發炎，展現PANX1作為炎症性疾病治療標靶的潛力。本成果為離子通道藥物開發與PANX1功能研究奠定重要基礎。 Pannexin 1 (PANX1) is a large-pore ion channel involved in apoptosis and purinergic signaling. Due to the poor selectivity of existing inhibitors, this study developed a novel, highly specific naphthyridone derivative that effectively inhibits PANX1 without off-target effects. The molecular mechanism and binding sites were elucidated. Using a DSS-induced mouse colitis model, the inhibitor was shown to alleviate intestinal inflammation, highlighting the therapeutic potential of targeting PANX1 for inflammatory diseases. This work lays a critical foundation for ion channel drug development and PANX1 research. |
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研究成果Result/Contributions |
Pannexin 1（PANX1）是一種大孔徑離子通道，在細胞凋亡、嘌呤訊號傳遞等多種重要生理反應中扮演關鍵角色。然而，目前市面上既有的PANX1抑制劑普遍存在選擇性低、抑制效果差的問題，容易造成基礎研究結果誤判，並限制其在基礎與轉譯醫學中的應用。因此，開發新型、具高專一性與高效能的PANX1抑制劑成為迫切需求。本研究在先前成果的基礎上，成功開發出一系列新型萘啶酮類衍生物，具備優異的PANX1抑制能力，並首次揭示其分子作用機制。透過藥物合成與優化、流式細胞儀篩選平台及電生理實驗，我們篩選出具有低IC50值的小分子抑制劑，且證明其不影響LRRC8/SWELL1通道及真核拓撲異構酶II，克服了以往抑制劑在細胞體積調控及肝毒性研究上的爭議。此外，結合結構活性關係分析、點突變與分子對接模擬，我們確立了藥物關鍵官能基與PANX1重要結合位點，並證明新型抑制劑在不同膜電位條件下仍可維持全面性抑制，為未來探究PANX1通道開關調控提供理論基礎。最後，透過DSS誘導的小鼠結腸炎模型，本研究首次證實PANX1抑制劑能有效緩解腸道發炎與病情惡化，進一步奠定PANX1作為治療發炎性腸病及其他免疫相關疾病（如慢性神經性疼痛、腦傷及缺血再灌注損傷）潛在靶點的重要性。 Pannexin 1 (PANX1) is a large-pore ion channel that plays a crucial role in various physiological processes such as apoptosis and purinergic signaling. However, commonly used PANX1 inhibitors generally suffer from low selectivity and poor efficacy, leading to potential misinterpretations in basic research and limiting their applications in both fundamental and translational studies. Therefore, there is an urgent need to develop novel inhibitors with high specificity and potency. Building upon our previous work, this study successfully developed a series of novel naphthyridone derivatives with excellent PANX1 inhibitory activity and, for the first time, elucidated their molecular mechanisms. Through drug synthesis and optimization, combined with flow cytometry-based screening and electrophysiological assays, we identified small-molecule inhibitors with significantly lower IC50 values compared to traditional agents, without affecting LRRC8/SWELL1 channels or eukaryotic topoisomerase II, thus addressing previous concerns regarding cell volume regulation and hepatotoxicity. Furthermore, by integrating structure-activity relationship analysis, site-directed mutagenesis, and molecular docking simulations, we defined the key functional groups and critical binding sites on PANX1, demonstrating that the new inhibitors maintain robust inhibition under varying membrane potentials, thereby laying the groundwork for further investigation into PANX1 gating mechanisms. Finally, using a DSS-induced murine colitis model, we provided the first evidence that PANX1 inhibition can effectively alleviate intestinal inflammation and disease severity, establishing PANX1 as a promising therapeutic target not only for inflammatory bowel diseases but also for other immune-related conditions such as chronic neuropathic pain, brain injury, and ischemia-reperfusion damage. |
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https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202411538 |
其他參考資料 Related Information |
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