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 eupatilinmediated 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.
Bibliographical noteFunding Information:
We thank Gou Young Koh for providing ERG equipment and Jaeryung Kim for technical support for ERG measurements. This study was supported by Korean Health Industry Development Institute grants (HI12C0014 and HI18C0013) funded by the Korean Ministry of Health and Welfare, Korean National Research Foundation grants (2015M3A9B6027820, 2015K1A1A2028365, 2015M3A9C4076321, and 2015M3A9B6027818) funded by the Korean Ministry of Science and ICT, and the Brain Korea 21Plus Project.
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