Review Article

Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead

Hong-Shuo Sun1,2,3,4, F. David Horgen5, Daniel Romo6, Kenneth G. Hull6,7, Sigrid A. Kiledal6, Andrea Fleig8, Zhong-Ping Feng2
1 Departments of Surgery, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
2 Departments of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
3 Departments of Pharmacology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
4 Leslie Dan Faculty of Pharmacy, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
5 Department of Natural Sciences, Hawaii Pacific University, Kaneohe, HI 96744, USA
6 Department of Chemistry & Biochemistry, Baylor University, Waco, TX 76798-7348, USA
7 The CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76798, USA
8 Center for Biomedical Research at The Queen’s Medical Center and John A. Burns School of Medicine and Cancer Center at the University of Hawaii, Honolulu, HI 96720, USA
Correspondence to: Hong-Shuo Sun: hss.sun@utoronto.ca, Zhong-Ping Feng: zp.feng@utoronto.ca,
DOI: 10.1038/s41401-020-00512-4
Received: 16 May 2020
Accepted: 17 August 2020
Advance online: 29 September 2020

Abstract

Ion channels are the third largest class of targets for therapeutic drugs. The pharmacology of ion channels is an important research area for identifying new treatment options for human diseases. The past decade or so has seen increasing interest in an ion channel protein belonging to the transient receptor potential (TRP) family, namely the melastatin subfamily member 7 (TRPM7), as an emerging drug target. TRPM7 is a bifunctional protein with a magnesium and calcium-conducting divalent ion channel fused with an active kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 provides a link between cellular metabolic status and intracellular calcium homeostasis in neurons due to TRPM7’s unique sensitivity to fluctuating intracellular Mg·ATP levels. Thus, the protein plays a key role in ischemic and hypoxic neuronal cell death and brain injury, and is one of the key nonglutamate mechanisms in cerebral ischemia and stroke. Currently, the most potent and specific TRPM7 inhibitor is waixenicin A, a xenicane diterpenoid from the Hawaiian soft coral Sarcothelia edmondsoni. Using waixenicin A as a pharmacological tool, we demonstrated that TRPM7 is involved in promoting neurite outgrowth in vitro. Most recently, we found that waixenicin A reduced hypoxic–ischemic brain injury and preserved long-term behavioral outcomes in mouse neonates. We here suggest that TRPM7 is an emerging drug target for CNS diseases and disorders, and waixenicin A is a viable drug lead for these disorders.
Keywords: ion channels; TRPM7; Waixenicin A; hypoxic–ischemic brain injury; stroke; neuroprotection; drug development

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