Discovery and Nanosized Preparations of (S, R)-Tylophorine Malate as Novel anti-SARS-CoV-2 Agents

Ziwen Wang; Fei Ye; Yue Feng; Wen Xiao; Hongjian Song; Li Zhao; Roujian Lu; Baoying Huang; Yuxiu Liu; Wenling Wang; Yongqiang Li; Yi Ding; Yanlong Zheng; Xiangrong Song; Wenjie Tan; Qingmin Wang

doi:10.1021/acsmedchemlett.1c00481

Discovery and Nanosized Preparations of (S, R)-Tylophorine Malate as Novel anti-SARS-CoV-2 Agents

ACS Med Chem Lett. 2021 Oct 24;12(11):1838-1844. doi: 10.1021/acsmedchemlett.1c00481. eCollection 2021 Nov 11.

Authors

Ziwen Wang^{1

2}, Fei Ye³, Yue Feng⁴, Wen Xiao⁴, Hongjian Song¹, Li Zhao³, Roujian Lu³, Baoying Huang³, Yuxiu Liu¹, Wenling Wang³, Yongqiang Li¹, Yi Ding^{1

5}, Yanlong Zheng¹, Xiangrong Song⁴, Wenjie Tan³, Qingmin Wang¹

Affiliations

¹ State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China.
² Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin 300387, China.
³ NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control and Prevention, China CDC, Beijing 102206, China.
⁴ Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
⁵ Shijiazhuang Lvfeng Chemical Co., Ltd., Shijiazhuang 052560, China.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has stimulated the search for effective drugs for its prevention and treatment. Natural products are an important source for new drug discovery. Here, we report that, NK007(S,R), a tylophorine malate, displays high antiviral activity against SARS-CoV-2 with an EC₅₀ 0.03 μM in vitro, which is substantially lower than that of remdesivir (EC₅₀: 0.8 μM in vitro), the only authorized drug to date. The histopathological research revealed that NK007(S,R) (5 mg/kg/dose) displayed a protection effect in lung injury induced by SARS-CoV-2, which is better than remdesivir (25 mg/kg/dose). We also prepared two nanosized preparations of NK007(S,R), which also showed good efficacy (EC₅₀: NP-NK007, 0.007 μM in vitro; LP-NK007, 0.014 μM in vitro). Our findings suggest that tylophora alkaloids, isolated from the traditional Chinese medicine Cynanchum komarovii AL, offer a new skeleton for the development of anticoronavirus drug candidate.