Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2
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Published:2023-04-24
Issue:1
Volume:8
Page:
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ISSN:2059-3635
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Container-title:Signal Transduction and Targeted Therapy
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language:en
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Short-container-title:Sig Transduct Target Ther
Author:
Xu ZhijianORCID, Shi Danrong, Han Jian-Bao, Ling Yun, Jiang Xiangrui, Lu Xiangyun, Li Chuan, Gong Likun, Ge Guangbo, Zhang Yani, Zang Yi, Song Tian-Zhang, Feng Xiao-Li, Tian Ren-Rong, Ji Jia, Zhu Miaojin, Wu Nanping, Wu Chunhui, Wang Zhen, Xu Yechun, Peng Cheng, Zheng MinORCID, Yang Junling, Du Feifei, Wu Junliang, Wang Peipei, Shen JingshanORCID, Zhang Jianliang, Zheng Yong-TangORCID, Yao HangpingORCID, Zhu WeiliangORCID
Abstract
AbstractEffective 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 (IC50 = 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 (EC50). 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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics
Reference48 articles.
1. WHO. Coronavirus Disease (COVID-2019) Situation Reports. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/ (2023). 2. Huang, T. et al. in Antiviral Drug Discovery and Development (eds Liu, X., Zhan, P., Menéndez-Arias, L. & Poongavanam, V.) 219–260 (Springer Singapore, 2021). 3. Gao, S. et al. Discovery and crystallographic studies of trisubstituted piperazine derivatives as non-covalent SARS-CoV-2 main protease inhibitors with high target specificity and low toxicity. J. Med. Chem. 65, 13343–13364 (2022). 4. Gao, S. et al. Medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors. Acta Pharm. Sin. B 12, 581–599 (2022). 5. Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021).
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