Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

Wang, Ruirui; Yang, Qinghua; Luo, Rong-Hua; Peng, Youmei; Dai, Shao‐Xing; Zhang, Xing-Jie; Chen, Huan; Cui, Xue-Qing; Liu, Yajuan; Huang, Jing‐Fei; Chang, Junbiao; Zheng, Yong‐Tang

doi:10.1371/journal.pone.0105617

Cited by 63 publications

(75 citation statements)

References 41 publications

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“…Previous studies have demonstrated that FNC is a potent inhibitor of HIV, HCV and HBV replication (32,34,35,38). In this study, we evaluated the cytotoxicity and antiviral activities of FNC as well as its analogs against multiple EVs, including EV71, CA16, CA6, on September 26, 2020 by guest http://jvi.asm.org/ Downloaded from EVD68, and CVB3, and observed that FNC showed relatively low cytotoxicity toward RD cells (safe dose of 1 μM), HEK293T cells (safe dose of μM) and MDCK cells (safe dose of 10 μM) ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that FNC, a nucleoside inhibitor, could significantly inhibit HCV, HIV, and HBV replication by blocking viral DNA or RNA synthesis (32,34,35,38). Here, we investigated whether FNC and its 7 chemical analogs inhibit EV71 infection ( Fig.…”

Section: The Inhibitory Effect Of Fnc and Its Derivatives On Ev71 Repmentioning

confidence: 99%

“…In addition, FNC inhibits cell proliferation and promotes apoptosis in a number of human cancer cell lines (36,37). Chang et al further proved that FNC possessed strong antiviral activity for human immunodeficiency virus (HIV) (38,39).…”

Section: Introductionmentioning

confidence: 99%

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The Pyrimidine Analog FNC Potently Inhibits the Replication of Multiple Enteroviruses

Yang

Zheng

et al. 2020

J Virol

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Human enteroviruses (EVs), including coxsackieviruses, the numbered enteroviruses, and echoviruses, cause a wide range of diseases, such as hand, foot, and mouth disease (HFMD), encephalitis, myocarditis, acute flaccid myelitis (AFM), pneumonia, and bronchiolitis. Therefore, broad-spectrum anti-EV drugs are urgently needed to treat EV infection. Here, we demonstrate that FNC (2'-deoxy-2'-β-fluoro-4'-azidocytidine), a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs, including enterovirus 71 (EV71), coxsackievirus A16 (CA16), CA6, EVD68, and coxsackievirus B3 (CVB3), at the nanomolar level. The antiviral mechanism of FNC involves mainly positive- and negative-strand RNA synthesis inhibition by targeting and competitively inhibiting the activity of EV71 viral RNA-dependent RNA polymerase (3Dpol), as demonstrated through quantitative real-time reverse transcription-PCR (RT-qPCR), in vitro 3Dpol activity, and isothermal titration calorimetry (ITC) experiments. We further demonstrated that FNC treatment every 2 days with 1 mg/kg of body weight in EV71 and CA16 infection neonatal mouse models successfully protected mice from lethal challenge with EV71 and CA16 viruses and reduced the viral load in various tissues. These findings provide important information for the clinical development of FNC as a broad-spectrum inhibitor of human EV pathogens. IMPORTANCE Human enterovirus (EV) pathogens cause various contagious diseases such as hand, foot, and mouth disease, encephalitis, myocarditis, acute flaccid myelitis, pneumonia, and bronchiolitis, which have become serious health threats. However, except for the EV71 vaccine on the market, there are no effective strategies to prevent and treat other EV pathogen infections. Therefore, broad-spectrum anti-EV drugs are urgently needed. In this study, we demonstrated that FNC, a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs at the nanomolar level. Further investigation revealed that FNC inhibits positive- and negative-strand RNA synthesis of EVs by interacting and interfering with the activity of EV71 viral RNA-dependent RNA polymerase (3Dpol). Our findings demonstrate for the first time that FNC is an effective broad-spectrum inhibitor for human EV pathogens.

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Section: Discussionmentioning

confidence: 99%

Section: The Inhibitory Effect Of Fnc and Its Derivatives On Ev71 Repmentioning

confidence: 99%

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The Pyrimidine Analog FNC Potently Inhibits the Replication of Multiple Enteroviruses

Yang

Zheng

et al. 2020

J Virol

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“…The inhibitory effect of samples on acuteHIV-1 NL4-3 infection was measured by the syncytia formation assay as described previously 55 . In the presence or absence of various concentrations of compounds, Therapeutic index (TI) was calculated by the ratio of CC 50 /EC 50 .…”

Section: Inhibition Of Syncytia Formationmentioning

confidence: 99%

“…The inhibitory effect of samples on acuteHIV-1 NL4-3 infection was measured by the syncytia formation assay as described previously 55…”

Section: Inhibition Of Syncytia Formationmentioning

confidence: 99%

Efficient repositioning of approved drugs as anti-HIV agents using Anti-HIV-Predictor

Dai

et al. 2016

Preprint

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Development of new, effective and affordable drugs against HIV is urgently needed. In this study, we developed a world’s first web server called Anti-HIV-Predictor (http://bsb.kiz.ac.cn:70/hivpre) for predicting anti-HIV activity of given compounds. This server is rapid and accurate (accuracy >93% and AUC > 0.958). We applied the server to screen 1835 approved drugs for anti-HIV therapy. Totally 67 drugs were predicted to have anti-HIV activity, 25 of which are anti-HIV drugs. Then we experimentally evaluated 35 predicted new anti-HIV compounds by assays of syncytia formation, p24 quantification, cytotoxicity. Finally, we repurposed 7 approved drugs (cetrorelix, dalbavancin, daunorubicin, doxorubicin, epirubicin, idarubicin and valrubicin) as new anti-HIV agents. The original indication of these drugs is involved in a variety of diseases such as female infertility and cancer. Anti-HIV-Predictor and the 7 repurposed anti-HIV agents provided here demonstrate the efficacy of this strategy for discovery of new anti-HIV agents.

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A Nearly 20‐Year Journey to Success of Azvudine for Antiviral Therapy

Chang

2023

Chin. J. Chem.

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Comprehensive SummaryModified nucleosides, particularly those with 4'‐modifications, are significant nucleosides used in antiviral treatments. The drug discovery campaign of Azvudine starts from 2′‐deoxynucleoside, followed by extensive modifications, such as introducing the 4’‐position substitutions, a 2’‐β‐fluoro atom, and changing the nucleobases. Azvudine acts potently toward various HIV‐1 strains by inhibiting HIV‐1 reverse transcription and preventing Vif‐induced A3G degradation, representing the first‐in‐class dual‐acting antiviral agent. In July 2021, NMPA conditionally approved Azvudine as an adjunct therapy for adult patients with high levels of HIV‐1 virus load when combined with NRTIs or NNRTIs. Azvudine is capable of inhibiting SARS‐CoV‐2, as well as its variants, including Alpha, Beta, Delta, and Omicron. Clinical trials reveal its real‐world effectiveness among hospitalized severely or critically ill COVID‐19 patients or those with pre‐existing conditions. On July 25th, 2022, the NMPA granted conditional authorization approving Azvudine as China's first domestic oral anti‐COVID‐19 agent. Generally, Azvudine at therapeutic doses is safe and well‐tolerated in clinical settings. Azvudine got approval from the National Health Commission and National Administration of Traditional Chinese Medicine on August 9th to be used in the "Diagnosis and Treatment Program for Novel Coronavirus Pneumonia (Ninth Edition)" for treating common COVID‐19 adult patients. On August 12th, 2022, it was also approved by the National Healthcare Security Administration to be added to the list of medical reimbursements. Of note, the achievements related to Azvudine were indexed in the China Basic Research Development Report in Thirty‐Five of 2022. Azvudine was also approved on January 5th, 2023, to be used in the "Diagnosis and Treatment Program for Novel Coronavirus Pneumonia (Tenth Edition)" for treating COVID‐19 patients. In February 2023, the Ministry of Health of the Russian Federation approved the usage of Azvudine among individuals infected with SARS‐CoV‐2.This article is protected by copyright. All rights reserved.

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Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

Cited by 63 publications

References 41 publications

The Pyrimidine Analog FNC Potently Inhibits the Replication of Multiple Enteroviruses

The Pyrimidine Analog FNC Potently Inhibits the Replication of Multiple Enteroviruses

Efficient repositioning of approved drugs as anti-HIV agents using Anti-HIV-Predictor

A Nearly 20‐Year Journey to Success of Azvudine for Antiviral Therapy

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