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Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality

Hao Li1, Lei-Ke Zhang 2,3,4, Shu-Fen Li2, Shao-Fei Zhang1, Wei-Wei Wan2, Yu-Lan Zhang2, Qi-Lin Xin2, Ke Dai1, Yuan-Yuan Hu1,Zhi-Bo Wang1
, Xiang-Tao Zhu 2,3, Yu-Jie Fang 2,3, Ning Cui5, Pan-He Zhang1, Chun Yuan5, Qing-Bin Lu6, Jie-Ying Bai7, Fei Deng 2,3,4,Geng-Fu Xiao 2,3,4, Wei Liu1 and Ke Peng 2,3,4

1State Key Laboratory of Pathogen and Biosecurity, Beijing Key Laboratory of Vector Borne and Natural Focus Infectious Diseases, Beijing Institute of Microbiology and
Epidemiology, Beijing 100071, China; 2State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China; 3University of
Chinese Academy of Sciences, Beijing 100049, China; 4Wuhan National Biosafety Laboratory, Mega-Science Center for Bio-Safety Research, Chinese Academy of Sciences, Wuhan,Hubei 430071, China; 5The 154 Hospital, People’s Liberation Army, Xinyang, Henan, China; 6School of Public Health, Peking University, Beijing, China and 7Laboratory Animal
Center, Academy of Military Medical Sciences, Beijing, China
* Correspondence: Wei Liu (liuwei@bmi.ac.cn) or Ke Peng (pengke@wh.iov.cn)These authors contributed equally: Hao Li, Lei-Ke Zhang.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious diseases by the World Health Organization due to its high fatality of 12%–50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.

Cell Research (2007) 17: 307-308. doi: 10.1038/cr.2007.29; published online 16 April 2007

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