SARS-CoV-2 3CLpro inhibits the replication of influenza viruses through the cleavage of NP and PA

Liubing Du; Xiaoyu Cai; Ziliang Peng; Mengxuan Wang; Huijie Li; Xue Liu; Zhihui Zhang; Manqi Cao; Shuchun Zhang; Zhenyu He; Zhanjia Zhang; Yu Yan; Qitong Lin; Yushan Xue; Deyin Guo; Ji-An Pan; Yao-Qing Chen; Xiaoxue Peng

doi:10.1016/j.virs.2026.08.006

August 2026

Citation: Liubing Du, Xiaoyu Cai, Ziliang Peng, Mengxuan Wang, Huijie Li, Xue Liu, Zhihui Zhang, Manqi Cao, Shuchun Zhang, Zhenyu He, Zhanjia Zhang, Yu Yan, Qitong Lin, Yushan Xue, Deyin Guo, Ji-An Pan, Yao-Qing Chen, Xiaoxue Peng. SARS-CoV-2 3CLpro inhibits the replication of influenza viruses through the cleavage of NP and PA .VIROLOGICA SINICA, 2026, 41(4) : 842-854. http://dx.doi.org/10.1016/j.virs.2026.08.006

SARS-CoV-2 3CLpro inhibits the replication of influenza viruses through the cleavage of NP and PA

Liubing Du ^a,b ,
Xiaoyu Cai ^c ,
Ziliang Peng ^a ,
Mengxuan Wang ^a ,
Huijie Li ^a ,
Xue Liu ^d ,
Zhihui Zhang ^a ,
Manqi Cao ^a ,
Shuchun Zhang ^a ,
Zhenyu He ^a ,
Zhanjia Zhang ^a ,
Yu Yan ^a ,
Qitong Lin ^a ,
Yushan Xue ^a ,
Deyin Guo ^b ,
Ji-An Pan ^{a,d
,,} ,
Yao-Qing Chen ^{c
,,} ,
Xiaoxue Peng ^{a,d,e
,,}

a. The Molecular Cancer Research Center, Zhongshan School of Medicine, Sun Yat-sen University Shenzhen Campus, Shenzhen 518107, China;
b. The Division of Basic Research, Guangzhou National Laboratory, Bio-island, Guangzhou 510320, China;
c. School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China;
d. The Center for Infection and Immunity Study, Zhongshan School of Medicine, Sun Yat-sen University Shenzhen Campus, Shenzhen 518107, China;
e. Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China

Corresponding author: Ji-An Pan, pengxx9@mail.sysu.edu.cn
Yao-Qing Chen, chenyaoqing@mail.sysu.edu.cn
Xiaoxue Peng, panjan@mail.sysu.edu.cn
Received Date: 01 April 2026
Accepted Date: 06 August 2026
Available online: 10 August 2026

Abstract

The co-circulation of multiple viruses can lead to distinct pathological outcomes, yet how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection influences other viral infections remains poorly understood, despite its documented high frequency during the pandemic. In this study, we investigated how the proteolytic activity of SARS-CoV-2 3C-like protease (3CLpro) influences the replication of influenza A virus. In silico analysis identified candidate 3CLpro cleavage sites across numerous viral proteins, and biochemical assays confirmed that 3CLpro catalyzes the degradation of influenza virus nucleoprotein (NP) and polymerase acidic protein (PA) in a manner requiring its protease activity. This degradation of NP and PA, which are essential for viral genome packaging and transcription, disrupted the influenza replicative cycle and suppressed viral replication, both upon ectopic 3CLpro expression and during SARS-CoV-2 infection. Our data uncover a direct, enzyme-based mechanism by which SARS-CoV-2 can suppress influenza virus replication during coinfection. We provide a molecular explanation for the sharp, global decline in influenza activity observed during the COVID-19 pandemic and illustrate how enzymatic weapons of one virus can be repurposed to restrain a competing pathogen.
- SARS-CoV-2
- , Influenza virus
- , 3C-like protease (3CLpro)
- , Nucleoprotein (NP)
- , Polymerase acidic protein (PA)

Electronic Supplementary Material

10.1016j.virs.2026.08.006-ESM3.xlsx
10.1016j.virs.2026.08.006-ESM1.docx
10.1016j.virs.2026.08.006-ESM2.xlsx

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