Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2

  1. Zhijian Xu
  2. Danrong Shi
  3. Jian-Bao Han
  4. Yun Ling
  5. Xiangrui Jiang
  6. Xiangyun Lu
  7. Chuan Li
  8. Likun Gong
  9. Guangbo Ge
  10. Yani Zhang
  11. Yi Zang
  12. Tian-Zhang Song
  13. Xiao-Li Feng
  14. Ren-Rong Tian
  15. Jia Ji
  16. Miaojin Zhu
  17. Nanping Wu
  18. Chunhui Wu
  19. Zhen Wang
  20. Yechun Xu
  21. Cheng Peng
  22. Min Zheng
  23. Junling Yang
  24. Feifei Du
  25. Junliang Wu
  26. Peipei Wang
  27. Jingshan Shen
  28. Jianliang Zhang
  29. Yong-Tang Zheng
  30. Hangping Yao
  31. Weiliang Zhu

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC 50  = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC 50 ). In comparison with vehicle-treated animals, rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals. At necropsy, nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude. A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center, which were randomized (1:1) to nelfinavir and control groups, showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days (9.0 vs. 14.5 days, P  = 0.055) and the duration of fever time by 3.8 days (2.8 vs. 6.6 days, P  = 0.014) in mild/moderate COVID-19 patients. The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients, together with its well-established good safety profile in almost all ages and during pregnancy, indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.

Article activity feed

  1. Version published to 10.1038/s41392-023-01429-0
  2. ScreenIT

    SciScore for 10.1101/2020.01.27.921627: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    2.1 Homology modelling: 43 Mpro complexes with ligands were downloaded from protein data bank6 (PDB IDs: 1WOF, 2A5I, 2A5K, 2ALV, 2AMD, 2GTB, 2GX4, 2GZ7, 2GZ8, 2OP9, 2QIQ, 2V6N, 2ZU4, 2ZU5, 3SN8, 3SND, 3SZN, 3TIT, 3TIU, 3TNS, 3TNT, 3V3M, 4F49, 4MDS, 4TWW, 4TWY, 4WY3, 4YLU, 4YOG, 4YOI, 4YOJ, 4ZRO, 5C5N, 5C5O, 5EU8, 5N5O, 5N19, 5NH0, 5WKJ, 5WKK, 5WKL, 5WKM,6FV1) and aligned to 2GTB in PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    7 11 complexes (PDB IDs: 2A5K, 2GTB, 2GX4, 3SND, 3TNS, 3V3M, 4F49, 4YLU, 5NH0, 5WKJ, 5WKM) were served as templates to build 11 2019-nCov Mpro models in SWISS-MODEL server by “user template” mode.8 2.2 Approved Drugs: 1905 approved small molecule drugs with 3D coordinates were downloaded from DrugBank release version 5.1.5,9 while 1903 drugs could be converted to pdbqt format by prepare_ligand4.py script in MGLToos version 1.5.6.10 2.3 Molecular Docking: 1903 approved drugs in pdbqt format were docked to 2019-nCov Mpro model (template: 2GTB) by smina,11 which is a fork of AutoDock Vina12 with improving scoring and minimization.
    DrugBank
    suggested: (DrugBank, RRID:SCR_002700)
    AutoDock
    suggested: (AutoDock, RRID:SCR_012746)
    General Amber force field (GAFF)15 and Amber ff03 force field16 were used to parameterize the ligand and protein, respectively. 10,000 steps of minimization with constraints (10 kcal/mol/Å2) on heavy atoms of complex, including 5,000 steps of steepest descent minimization and 5,000 steps of conjugate gradient minimization, was used to optimize each system.
    Amber
    suggested: (AMBER, RRID:SCR_016151)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.01.27.921627v1 on bioRxiv