Open AccessIdentification of Sclareol As a Natural Neuroprotective Ca v 1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery
Author(s) -
Wang Hui,
Xie Mingqi,
Rizzi Giorgio,
Li Xin,
Tan Kelly,
Fussenegger Martin
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202102855
Subject(s) - substantia nigra , drug discovery , nfat , pharmacology , in silico , virtual screening , dopaminergic , reporter gene , biology , chemistry , neuroscience , gene expression , biochemistry , dopamine , gene , transcription factor
Parkinson's disease (PD) results from selective loss of substantia nigra dopaminergic (SNc DA) neurons, and is primarily caused by excessive activity‐related Ca 2+ oscillations. Although L‐type voltage‐gated calcium channel blockers (CCBs) selectively inhibiting Ca v 1.3 are considered promising candidates for PD treatment, drug discovery is hampered by the lack of high‐throughput screening technologies permitting isoform‐specific assessment of Cav‐antagonistic activities. Here, a synthetic‐biology‐inspired drug‐discovery platform enables identification of PD‐relevant drug candidates. By deflecting Cav‐dependent activation of nuclear factor of activated T‐cells (NFAT)‐signaling to repression of reporter gene translation, they engineered a cell‐based 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‐learning 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‐cell patch‐clamp recordings confirmed that sclareol inhibits Ca v 1.3 more strongly than Ca v 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.