期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 8, 页码 3642-3648出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99232
关键词
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资金
- Korean Health Industry Development Institute - Korean Ministry of Health and Welfare [HI12C0014, HI18C0013]
- Korean National Research Foundation - Korean Ministry of Science and ICT [2015M3A9B6027820, 2015K1A1A2028365, 2015M3A9C4076321, 2015M3A9B6027818]
- Brain Korea 21Plus Project
- National Research Foundation of Korea [2015M3A9C4076321, 2015M3A9B6027818, 2015K1A1A2028365, 2015M3A9B6027820] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.
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