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Although L\u2010type voltage\u2010gated calcium channel blockers (CCBs) selectively inhibiting Ca<jats:sub>v<\/jats:sub>1.3 are considered promising candidates for PD treatment, drug discovery is hampered by the lack of high\u2010throughput screening technologies permitting isoform\u2010specific assessment of Cav\u2010antagonistic activities. Here, a synthetic\u2010biology\u2010inspired drug\u2010discovery platform enables identification of PD\u2010relevant drug candidates. By deflecting Cav\u2010dependent activation of nuclear factor of activated T\u2010cells (NFAT)\u2010signaling to repression of reporter gene translation, they engineered a cell\u2010based assay where reporter gene expression is activated by putative CCBs. By using this platform in combination with in silico virtual screening and a trained deep\u2010learning neural network, sclareol is identified from a essential oils library as a structurally distinctive compound that can be used for PD pharmacotherapy. In vitro studies, biochemical assays and whole\u2010cell patch\u2010clamp recordings confirmed that sclareol inhibits Ca<jats:sub>v<\/jats:sub>1.3 more strongly than Ca<jats:sub>v<\/jats:sub>1.2 and decreases firing responses of SNc DA neurons. In a mouse model of PD, sclareol treatment reduced DA neuronal loss and protected striatal network dynamics as well as motor performance. Thus, sclareol appears to be a promising drug candidate for neuroprotection in PD patients.<\/jats:p>","DOI":"10.1002\/advs.202102855","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T05:19:09Z","timestamp":1642483149000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Identification of Sclareol As a Natural Neuroprotective Ca<sub>v<\/sub>1.3\u2010Antagonist Using Synthetic Parkinson\u2010Mimetic Gene Circuits and Computer\u2010Aided Drug Discovery"],"prefix":"10.1002","volume":"9","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel 4058 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-532X","authenticated-orcid":false,"given":"Mingqi","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel 4058 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Klingelbergstrasse 50\/70 Basel 4056 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel 4058 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"Tan","sequence":"additional","affiliation":[{"name":"Biozentrum University of Basel  Klingelbergstrasse 50\/70 Basel 4056 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-667X","authenticated-orcid":false,"given":"Martin","family":"Fussenegger","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich  Mattenstrasse 26 Basel 4058 Switzerland"},{"name":"University of Basel Faculty of Science  Mattenstrasse 26 Basel CH\u20104058 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-39480-z"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(03)00176-7"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17060904"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2006.11.011"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2016.07.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-10-04081.2003"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.04.007"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.412"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2946-16.2017"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-16-05944.2001"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2005-0888"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2015.1048936"},{"key":"e_1_2_9_13_1","first-page":"507","volume":"19","author":"Xie M.","year":"2018","journal-title":"Mol. 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