2. Academic Validation
  3. Novel derivatives of brincidofovir and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine inhibit orthopoxviruses and human adenoviruses more potently than brincidofovir

Novel derivatives of brincidofovir and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine inhibit orthopoxviruses and human adenoviruses more potently than brincidofovir

  • Signal Transduct Target Ther. 2025 Apr 11;10(1):114. doi: 10.1038/s41392-025-02207-w.
Yifan Zhang # 1 2 3,  Yanmin Wan # 4 5,  Cuiyuan Guo # 2 6,  Zhaoqin Zhu # 2 7,  Chao Qiu # 8,  Jiasheng Lu 3 9 10,  Yanan Zhou 11,  Jiaojiao Zheng 7,  Fahui Dai 7,  Xiaoyang Cheng 1 2,  Kunlu Deng 1 2,  Wanhai Wang 6,  Youchun Wang 12 13,  Wenhong Zhang 14
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China.
  • 2 Department of laboratory medicine, Shanghai Public Health Clinical Center, Shanghai, China.
  • 3 School of Life Sciences, Fudan University, Shanghai, China.
  • 4 Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China. yanmin_wan@fudan.edu.cn.
  • 5 Department of radiology, Shanghai Public Health Clinical Center, Shanghai, China. yanmin_wan@fudan.edu.cn.
  • 6 Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, China.
  • 7 Biosafety Level 3 Laboratory, Shanghai Public Health Clinical Center, Shanghai, China.
  • 8 Institutes of biomedical sciences & Shanghai Key Laboratory of Medical Epigenetics, Fudan University, Shanghai, China.
  • 9 Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 10 Risen (Shanghai) Pharma Tech Co. Ltd., Shanghai, China.
  • 11 Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.
  • 12 Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China. wangyc@nifdc.org.cn.
  • 13 Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education; State Key Laboratory of Respiratory Health and Multimorbidity, Beijing, China. wangyc@nifdc.org.cn.
  • 14 Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China. zhangwenhong@fudan.edu.cn.
  • # Contributed equally.
PMID: 40210872 DOI: 10.1038/s41392-025-02207-w
Abstract

Brincidofovir (BCV) and tecovirimat are the only two chemical drugs that have been approved to treat smallpox and can be requested for monkeypox (Mpox) treatment through a single-patient Emergency Investigational New Drug (EIND) application. Disappointedly, the efficacy of tecovirimat manifested in recent clinical trials is far from being satisfactory, while the clinical efficacy of BCV is still inconclusive. Given that monkeypox virus (MPXV), variola and Other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the Antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPC, cidofovir) or (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA). We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV. Most strikingly, the EC50 and EC90 of ODE-(S)-HPMPA formate against MPXV were more than 40-fold lower than those of BCV. In contrast, we observed that the anti-herpes simplex virus type 1 (HSV-1) activities of the (S)-HPMPA-based prodrugs were less effective than those of the cidofovir-based prodrugs (BCV and BCV formate), especially in vivo. Moreover, we showed for the first time that cytidine and adenine analog combined therapies could provide mice with complete protection against lethal challenges of both vaccinia and HSV-1. Collectively, we propose that both the ODE-(S)-HPMPA formate and the BCV/ODE-(S)-HPMPA formate combination are worth further investigations for their potential clinical applications.

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