Citation: Hongliang Wang, Yuanguo Li, Linjie Yan, Liyuan Ge, Wenhao Wang, Lei Zhao, Yuwei Gao, Wu Zhong. Discovery of DHODH PROTAC degraders with anti-SARS-CoV-2 and influenza virus activity[J]. Chinese Chemical Letters, ;2026, 37(8): 111751. doi: 10.1016/j.cclet.2025.111751 shu

Discovery of DHODH PROTAC degraders with anti-SARS-CoV-2 and influenza virus activity

Hongliang Wang ^{a, b, 1} ,
Yuanguo Li ^{c, 1} ,
Linjie Yan ^a ,
Liyuan Ge ^d ,
Wenhao Wang ^c ,
Lei Zhao ^{a, *,} ,
Yuwei Gao ^{c, *,} ,
Wu Zhong ^{a, *,}

a.
National Engineering Research Center for the Emergency Drug, Beijing 100850, China
b.
Army Medical University, NCO School, Shijiazhuang 050000, China
c.
Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, State Key Laboratory of Pathogen and Biosecurity, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, China
d.
Song Li′s Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572024, China

leizhao-hit@hotmail.com

dawei1105@foxmail.com

zhongwu@bmi.ac.cn

Received Date: 28 June 2025
Revised Date: 22 August 2025
Accepted Date: 24 August 2025
Available Online: 25 August 2025

Figures(5)

Coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus exacerbates pulmonary inflammation and tissue damage, significantly increasing the risks of respiratory failure, acute respiratory distress syndrome (ARDS), and secondary bacterial infections. Currently, there are no approved therapeutic agents specifically targeting these two viruses' coinfection. Human dihydroorotate dehydrogenase (DHODH), a key enzyme catalyzing the fourth step in the de novo pyrimidine biosynthesis pathway through the oxidation of dihydroorotate to orotate, serves as the rate-limiting enzyme in pyrimidine biosynthesis. This critical metabolic checkpoint has emerged as a promising broad-spectrum antiviral target. In this study, we designed and synthesized a series of DHODH-targeting proteolysis-targeting chimeras (PROTACs), among which PROTACs 17 and 19 connected via flexible alkyl linkers were identified as the most potent molecules. Mechanistic investigations revealed that 17 and 19 induced DHODH degradation through the proteasome- and cereblon (CRBN)-dependent pathways. Remarkably, 17 and 19 exhibited significant antiviral activities against both influenza virus and SARS-CoV-2 in vitro. These findings collectively present a novel and effective strategy for the treatment of coinfection caused by SARS-CoV-2 and influenza virus.
- DHODH,
- PROTAC,
- SARS-CoV-2,
- Influenza virus,
- Coinfection
1. [1]
  S. Liu, W. Li, S. Jiang, J. Med. Virol. 94 (2022) 4056–4057. doi: 10.1002/jmv.27874
2. [2]
  M. Golpour, Jalali H, R. Alizadeh-Navaei, et al., BMC Infect. Dis. 25 (2025) 145. doi: 10.1186/s12879-025-10521-5
3. [3]
  K.L. Mai, W.Q. Pan, S.L. Zheng, et al., Adv. Biotechnol. 3 (2025) 5. doi: 10.1007/s44307-025-00057-9
4. [4]
  M.C. Swets, C.D. Russell, E.M. Harrison, et al., Lancet 399 (2022) 1463–1464. doi: 10.1016/S0140-6736(22)00383-X
5. [5]
  G.W. Pratt, C.L. Wong, L.V. Rao, APMIS 133 (2025) e70010. doi: 10.1111/apm.70010
6. [6]
  H.C. Maltezou, A. Papanikolopoulou, S. Vassiliu, et al., Viruses 15 (2023) 865. doi: 10.3390/v15040865
7. [7]
  L. Bai, Y.L. Zhao, J.Z. Dong, et al., Cell Res. 31 (2021) 395–403. doi: 10.1038/s41422-021-00473-1
8. [8]
  Y. Zhou, L. Tao, X. Zhou, et al., Cancer Metab. 9 (2021) 22. doi: 10.1109/3m-nano49087.2021.9599826
9. [9]
  J. Fang, T. Uchiumi, M. Yagi, et al., Biosci. Rep. 33 (2013) e00021. doi: 10.1042/BSR20120097
10. [10]
  V.K. Vyas, M. Ghate, Mini Rev. Med. Chem. 11 (2011) 1039–1055. doi: 10.2174/138955711797247707
11. [11]
  F. Zeng, S. Li, G. Yang, et al., Acta Pharm. Sin. B 11 (2021) 795–809. doi: 10.1016/j.apsb.2020.10.008
12. [12]
  R. Xiong, L.K. Zhang, S.L. Li, et al., Protein Cell 13 (2022) 778. doi: 10.1007/s13238-020-00801-y
13. [13]
  Y.C. Zheng, S.L. Li, K. Song, et al., Viruses 14 (2022) 928. doi: 10.3390/v14050928
14. [14]
  M. Qing, G. Zou, Q.Y. Wang, et al., Antimicrob. Agents Chemother. 54 (2010) 3686–3695. doi: 10.1128/AAC.00561-10
15. [15]
  P.I. Andersen, K. Krpina, A. Ianevski, et al., Viruses 11 (2019) 964. doi: 10.3390/v11100964
16. [16]
  D. Morales Vasquez, J.G. Park, G. Ávila-Pérez, et al., Viruses 12 (2020) 1041. doi: 10.3390/v12091041
17. [17]
  P. Luthra, J. Naidoo, C.A. Pietzsch, et al., Antiviral Res. 158 (2018) 288–302. doi: 10.1016/j.antiviral.2018.08.012
18. [18]
  H. Fu, Z. Zhang, Y. Dai, et al., Am. J. Transl. Res. 12 (2020) 8247–8255.
19. [19]
  J. Luban, R.A. Sattler, E. Mühlberger, et al., Virus Res. 292 (2021) 198246. doi: 10.1016/j.virusres.2020.198246
20. [20]
  W. Zhong, X.B. Zhou, R.Y. Cao, et al., Patent, US2022193039A1, 2020.
21. [21]
  R.A. Ward, S. Fawell, N. Floc'h, et al., Chem. Rev. 121 (2021) 3297–3351. doi: 10.1021/acs.chemrev.0c00383
22. [22]
  Y. Yang, S. Li, Y. Wang, et al., Signal Transduct. Target Ther. 7 (2022) 329. doi: 10.1038/s41392-022-01168-8
23. [23]
  M. Békés, D.R. Langley, C.M. Crews, Nat. Rev. Drug Discov. 21 (2022) 181–200. doi: 10.1038/s41573-021-00371-6
24. [24]
  M. Konstantinidou, J.Y. Li, B.D. Zhang, et al., Expert. Opin Drug Discov. 14 (2019) 1255–1268. doi: 10.1080/17460441.2019.1659242
25. [25]
  K. Li, C.M. Crews, Chem. Soc. Rev. 51 (2022) 5214–5236. doi: 10.1039/d2cs00193d
26. [26]
  L. Zhao, J. Zhao, K.H. Zhong, et al., Signal Transduct. Target. Ther. 7 (2022) 113. doi: 10.1007/978-981-16-9515-5_9
27. [27]
  K.L. Li, G.Q. Dong, S.C. Wu, et al., Chin. Chem. Lett. 36 (2025) 110280. doi: 10.1016/j.cclet.2024.110280
28. [28]
  Y.Y. Yang, H.R. Xie, X.B. Yu, et al., Chin. Chem. Lett. 35 (2024) 109570. doi: 10.1016/j.cclet.2024.109570
29. [29]
  S.B. Alabi, C.M. Crews, J. Biol. Chem. 296 (2021) 100647. doi: 10.1016/j.jbc.2021.100647
30. [30]
  H.Y. Zhao, M.H. Xin, S.Q. Zhang, Drug Dev. Res. 84 (2023) 337–394. doi: 10.1002/ddr.22026
31. [31]
  Z.Y. Kang, S. Li, Y. Li, et al., Chin. Chem. Lett. 36 (2025) 110447. doi: 10.1016/j.cclet.2024.110447
32. [32]
  X.Y. Shao, S.J. Xu, X.F. Wan, et al., Chin. Chem. Lett. 34 (2023) 108349. doi: 10.1016/j.cclet.2023.108349
33. [33]
  S. Christian, C. Merz, L. Evans, et al., Leukemia 33 (2019) 2403–2415. doi: 10.1038/s41375-019-0461-5
34. [34]
  K.M. Stegmann, A. Dickmanns, N. Heinen, et al., iScience 25 (2022) 104293. doi: 10.1016/j.isci.2022.104293
35. [35]
  T.A. Bemis, J. La Clair, M.D. Burkart, J. Med. Chem. 64 (2021) 8042–8052. doi: 10.1021/acs.jmedchem.1c00482
36. [36]
  K. Cyrus, M. Wehenkel, E.Y. Choi, et al., Mol. BioSyst. 7 (2011) 359–364. doi: 10.1039/C0MB00074D
37. [37]
  V. Poongavanam, Y. Atilaw, S. Siegel, et al., J. Med. Chem. 65 (2022) 13029–13040. doi: 10.1021/acs.jmedchem.2c00877
38. [38]
  A. Bricelj, Y.L. Dora Ng, D. Ferber, et al., ACS Med. Chem. Lett. 12 (2021) 1733–1738. doi: 10.1021/acsmedchemlett.1c00368
39. [39]
  V. Poongavanam, B.C. Doak, J. Kihlberg, Curr. Opin. Chem. Biol. 44 (2018) 23–29.
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沈阳化工大学材料科学与工程学院沈阳 110142