Identification of Sclareol As a Natural Neuroprotective Cav1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery

Abstract

Abstract Parkinson's disease (PD) results from selective loss of substantia nigra dopaminergic (SNc DA) neurons, and is primarily caused by excessive activity‐related Ca2+ oscillations. Although L‐type voltage‐gated calcium channel blockers (CCBs) selectively inhibiting Cav1.3 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 Cav1.3 more strongly than Cav1.2 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.

Keywords

• drug discovery
• neuroprotection
• Parkinson's disease
• sclareol
• synthetic biology
• voltage‐gated calcium channels