MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its rod-and-ring assemblies

Qian Sun; Kesen Liu; Wandi Cao; Chengyue Wu; Hanhua Zhang; Xingya Wang; Chen Peng; Jie Sun; Anbing Zhang; Zhuo Zhou; Xing Liu

doi:10.1016/j.virs.2026.07.009

August 2026

Citation: Qian Sun, Kesen Liu, Wandi Cao, Chengyue Wu, Hanhua Zhang, Xingya Wang, Chen Peng, Jie Sun, Anbing Zhang, Zhuo Zhou, Xing Liu. MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its rod-and-ring assemblies .VIROLOGICA SINICA, 2026, 41(4) : 923-936. http://dx.doi.org/10.1016/j.virs.2026.07.009

MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its rod-and-ring assemblies

Qian Sun ^a ,
Kesen Liu ^b ,
Wandi Cao ^b ,
Chengyue Wu ^b ,
Hanhua Zhang ^b ,
Xingya Wang ^b ,
Chen Peng ^c ,
Jie Sun ^d ,
Anbing Zhang ^{e
,,} ,
Zhuo Zhou ^{f
,,} ,
Xing Liu ^{b
,,}

a. School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518060, China;
b. Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, The Belt & Road Shenzhen-Almaty Joint Laboratory for Frontiers of Medical Science (B&RsalFMS), Department of Pathogen Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518060, China;
c. National Key Laboratory of Veterinary Public Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
d. Shenzhen Customs Animal and Plant Inspection and Quarantine Technology Centre, Shenzhen 518026, China;
e. Department of Pulmonary and Critical Care Medicine, Zhongshan City People's Hospital, Zhongshan 528403, China;
f. State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215128, China

Corresponding author: Anbing Zhang, zhongshanzab@126.com
Zhuo Zhou, zhouzhuo@cams.cn
Xing Liu, xingliu1@szu.edu.cn
Received Date: 23 June 2026
Accepted Date: 17 July 2026
Available online: 23 July 2026

Abstract

Monkeypox virus (MPXV), a pathogenic orthopoxvirus, has caused major outbreaks and emerged as a global public health threat. Although antivirals approved for smallpox are used therapeutically against monkeypox, their clinical utility is limited by drug availability and emerging resistance. The conserved strategy by which viruses remodel host nucleotide metabolism to secure biosynthetic precursors for replication and spread has emerged as a pivotal target for the development of broad-spectrum antiviral therapeutics. In this study, leveraging the high genetic and biological similarity between vaccinia virus (VACV) and MPXV, we employed VACV as a surrogate model to screen 10 FDA-approved inhibitors targeting nucleotide metabolism enzymes, aiming to identify potential novel inhibitors against MPXV. Mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase type II (IMPDH2) inhibitor, displayed potent inhibition effects against both VACV and MPXV. Subsequent downstream time-course studies revealed that MMF targets a post-entry stage of the viral replication cycle. Mechanistic studies suggest that MMF inhibits IMPDH2 activity by suppressing ubiquitin-specific protease 5 (USP5)-mediated deubiquitination of IMPDH2 and inducing rod-and-ring (R&R) assembly, leading to reducing dNTP pools and enhancing antiviral effects. In conclusion, our findings demonstrate that MMF is an effective antiviral drug against VACV and MPXV infection and establish a host-directed therapeutic strategy to combat future orthopoxvirus outbreaks.
- Mycophenolate mofetil (MMF)
- , IMPDH2
- , Ubiquitin-specific protease 5 (USP5)
- , Rod/ring structures
- , Vaccinia virus
- , Monkeypox virus (MPXV)

Electronic Supplementary Material

10.1016j.virs.2026.07.009-ESM2.xlsx

10.1016j.virs.2026.07.009-ESM1.docx
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