1. Academic Validation
  2. Natural cardenolides suppress coronaviral replication by downregulating JAK1 via a Na+/K+-ATPase independent proteolysis

Natural cardenolides suppress coronaviral replication by downregulating JAK1 via a Na+/K+-ATPase independent proteolysis

  • Biochem Pharmacol. 2020 Oct;180:114122. doi: 10.1016/j.bcp.2020.114122.
Cheng-Wei Yang 1 Hsing-Yu Hsu 1 Hsin-Yu Chang 1 Yue-Zhi Lee 1 Shiow-Ju Lee 2
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan, ROC.
  • 2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan, ROC. Electronic address: slee@nhri.org.tw.
Abstract

An unprecedented biological function of natural cardenolides independent of their membrane target Na+/K+-ATPase is disclosed. Previously, we reported that cardenolides impart anti-transmissible gastroenteritis coronavirus (anti-TGEV) activity through the targeting of Na+/K+-ATPase and its associated PI3K_PDK1_RSK2 signaling. Swine testis cells with Na+/K+-ATPase α1 knocked down exhibited decreased susceptibility to TGEV infectivity and attenuated PI3K_PDK1_RSK2 signaling. Herein, we further explored a Na+/K+-ATPase-independent signaling axis induced by natural cardenolides that also afforded significant anti-coronaviral activity for porcine TGEV and human HCoV-OC43. Using pharmacological inhibition and gene silencing techniques, we found that this anti-TGEV or anti-HCoV-OC43 activity was caused by JAK1 proteolysis and mediated through upstream activation of Ndfip1/2 and its effector NEDD4. This study provides novel insights into the pharmacological effects of natural cardenolides, and is expected to inform their future development as Antiviral agents.

Keywords

Coronavirus; Janus kinase; NEDD4; Na(+)/K(+)-ATPase; Ouabain; Proteolysis.

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