Identification of Sclareol As a Natural Neuroprotective Cav1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery. Issue 7 (18th January 2022)

• Record Type: Journal Article
• Authors: Wang, Hui; Xie, Mingqi; Rizzi, Giorgio; Li, Xin; Tan, Kelly; Fussenegger, Martin
• Is Part Of: Advanced science. Volume 9:Issue 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-18
• Subjects: drug discovery -- neuroprotection -- Parkinson's disease -- sclareol -- synthetic biology -- voltage‐gated calcium channels; Science -- Periodicals; 505
• DOI: 10.1002/advs.202102855
• Languages: English
• ISSNs: 2198-3844

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 Ca 2+ oscillations. Although L‐type voltage‐gated calcium channel blockers (CCBs) selectively inhibiting Cav 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 Cav 1.3 more strongly than Cav 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. Abstract : High‐throughput, multiplexed quantification of CaV ‐mediated cell responses using synthetic gene circuits combined with in silico virtual screening and deep‐learning‐based prediction identified sclareol as a novel Cav 1.3‐antagonist that could evolve as neuroprotective pharmacotherapy of Parkinson's disease in the future.