首页|PA-E18G substitution in influenza A virus confers resistance to ZX-7101,a cap-dependent endonuclease inhibitor

PA-E18G substitution in influenza A virus confers resistance to ZX-7101,a cap-dependent endonuclease inhibitor

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Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101 A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50％effective con-centration(EC50)was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant pro-tection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.

Influenza virusCap-dependent endonuclease(CEN)Baloxavir marboxil(BXM)Drug resistance

Dan Luo、Qing Ye、Rui-Ting Li、Hang-Yu Zhou、Jing-Jing Guo、Suo-Qun Zhao、Sen Zhang、Tao Jiang、Yong-Qiang Deng、Cheng-Feng Qin

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State Key Laboratory of Pathogen and Biosecurity,Beijing Institute of Microbiology and Epidemiology,Academy of Military Medical Sciences,Beijing 100071,China

State Key Laboratory of Medical Molecular Biology,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences & Peking Union Medical College,Suzhou 215123,China

National Science and Technology Major ProjectKey-Area Research and Development Program of Guangdong ProvinceNational Natural Science Foundation of China(NSFC)National Natural Science Foundation of China(NSFC)National Science Fund for Distinguished Young ScholarsInnovative Research Group of the NSFCInnovation Fund for Medical Sciences of the Chinese Academy of Medical Sciences

2018ZX097110003-005-0022022B1111020002321701598217405581925025816210052019-I2M-5-049

2023

10.1016/j.virs.2023.06.002

中国病毒学
中国科学院武汉病毒研究所，中国微生物学会

中国病毒学

CSTPCDCSCD
影响因子：0.393
ISSN：1674-0769
年,卷(期)：2023.38(4)
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