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Volume 27
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10.3390/ijms27010300
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Triterpenoids CDDO and CDDO-EA Inhibit the Replication of Hepatitis B Virus by Modulating Nucleocapsid Assembly

by
Qiang Gao
1,
Ge Yang
1,
Ya Wang
1,
Lu Yang
1,
Jin Hu
1,
Huiqiang Wang
1,
Haiyan Yan
1,
Kun Wang
1,
Shuo Wu
1,2,*,
Yuhuan Li
1,2 and
Jiandong Jiang
1,2,*
1
CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(1), 300; https://doi.org/10.3390/ijms27010300 (registering DOI)
Submission received: 21 November 2025 / Revised: 22 December 2025 / Accepted: 24 December 2025 / Published: 27 December 2025
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Versions Notes

Abstract

Chronic hepatitis B virus (HBV) infection remains a global public health challenge, and the currently approved medications can not achieve a cure. Synthetic triterpenoids have shown promising therapeutic potential for liver pathologies. In our search for novel antiviral agents against HBV, we found that two triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and CDDO-ethyl amide (CDDO-EA), significantly inhibited HBV DNA replication. Further mechanistic investigation indicated that these two compounds did not significantly alter the levels of total HBV pgRNA, but dramatically reduced extracellular pgRNA and intracellular encapsidated pgRNA in a dose-dependent manner. Western blot analysis indicated minimal effects on core protein expression. Interestingly, using a particle gel assay, we observed that CDDO and CDDO-EA promoted the formation of empty capsids with no alteration in electrophoretic mobility. Moreover, we demonstrated that both compounds modulated the phosphorylation status of the core protein. Further cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) assay, and molecular docking analyses collectively suggested that CDDO and CDDO-EA could bind directly to the dimer–dimer interfaces of HBV core protein. Finally, a synergistic effect was observed between CDDO-EA and lamivudine in reducing intracellular and extracellular HBV DNA levels. Our findings indicate that triterpenoids CDDO and CDDO-EA are new mechanistically type of HBV capsid assembly modulators and warranted for further development as lead compounds against HBV.
Keywords: hepatitis B virus; triterpenoids; nucleocapsid assembly hepatitis B virus; triterpenoids; nucleocapsid assembly

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MDPI and ACS Style

Gao, Q.; Yang, G.; Wang, Y.; Yang, L.; Hu, J.; Wang, H.; Yan, H.; Wang, K.; Wu, S.; Li, Y.; et al. Triterpenoids CDDO and CDDO-EA Inhibit the Replication of Hepatitis B Virus by Modulating Nucleocapsid Assembly. Int. J. Mol. Sci. 2026, 27, 300. https://doi.org/10.3390/ijms27010300

AMA Style

Gao Q, Yang G, Wang Y, Yang L, Hu J, Wang H, Yan H, Wang K, Wu S, Li Y, et al. Triterpenoids CDDO and CDDO-EA Inhibit the Replication of Hepatitis B Virus by Modulating Nucleocapsid Assembly. International Journal of Molecular Sciences. 2026; 27(1):300. https://doi.org/10.3390/ijms27010300

Chicago/Turabian Style

Gao, Qiang, Ge Yang, Ya Wang, Lu Yang, Jin Hu, Huiqiang Wang, Haiyan Yan, Kun Wang, Shuo Wu, Yuhuan Li, and et al. 2026. "Triterpenoids CDDO and CDDO-EA Inhibit the Replication of Hepatitis B Virus by Modulating Nucleocapsid Assembly" International Journal of Molecular Sciences 27, no. 1: 300. https://doi.org/10.3390/ijms27010300

APA Style

Gao, Q., Yang, G., Wang, Y., Yang, L., Hu, J., Wang, H., Yan, H., Wang, K., Wu, S., Li, Y., & Jiang, J. (2026). Triterpenoids CDDO and CDDO-EA Inhibit the Replication of Hepatitis B Virus by Modulating Nucleocapsid Assembly. International Journal of Molecular Sciences, 27(1), 300. https://doi.org/10.3390/ijms27010300

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