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Azvudine

(Synonyms: RO-0622) 目录号 : GC25117

Azvudine (RO-0622) is a novel nucleoside reverse transcriptase inhibitor with antiviral activity against human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), potently inhibits HIV-1 (EC50 range 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM).

Azvudine Chemical Structure

Cas No.:1011529-10-4

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5mg
¥1,314.00
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25mg
¥3,939.00
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产品描述

Azvudine (RO-0622) is a novel nucleoside reverse transcriptase inhibitor with antiviral activity against human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), potently inhibits HIV-1 (EC50 range 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM).

[1] Wang RR, et al. PLoS One. 2014 Aug 21;9(8):e105617.

Chemical Properties

Cas No. 1011529-10-4 SDF Download SDF
别名 RO-0622
分子式 C9H11FN6O4 分子量 286.22
溶解度 DMSO: 57 mg/mL (199.15 mM);Water: 57 mg/mL (199.15 mM);Ethanol: 57 mg/mL (199.15 mM) 储存条件 Store at -20°C
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1 mM 3.4938 mL 17.4691 mL 34.9382 mL
5 mM 0.6988 mL 3.4938 mL 6.9876 mL
10 mM 0.3494 mL 1.7469 mL 3.4938 mL
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Research Update

Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients

Signal Transduct Target Ther 2021 Dec 6;6(1):414.PMID:34873151DOI:10.1038/s41392-021-00835-6.

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

A Randomized, Open-Label, Controlled Clinical Trial of Azvudine Tablets in the Treatment of Mild and Common COVID-19, a Pilot Study

Adv Sci (Weinh) 2020 Oct;7(19):e2001435.PMID:35403380DOI:10.1002/advs.202001435.

Coronavirus disease 2019 (COVID-19) has spread worldwide. To date, no specific drug for COVID-19 has been developed. Thus, this randomized, open-label, controlled clinical trial (ChiCTR2000029853) was performed in China. A total of 20 mild and common COVID-19 patients were enrolled and randomly assigned to receive Azvudine and symptomatic treatment (FNC group), or standard antiviral and symptomatic treatment (control group). The mean times of the first nucleic acid negative conversion (NANC) of ten patients in the FNC group and ten patients in the control group are 2.60 (SD 0.97; range 1-4) d and 5.60 (SD 3.06; range 2-13) d, respectively (p = 0.008). The mean times of the first NANC of four newly diagnosed subjects in the FNC group and ten subjects in the control group are 2.50 (SD 1.00; range 2-4) d and 9.80 (SD 4.73; range 3-19) d, respectively (starting from the initial treatment) (p = 0.01). No adverse events occur in the FNC group, while three adverse events occur in the control group (p = 0.06). The preliminary results show that FNC treatment in the mild and common COVID-19 may shorten the NANC time versus standard antiviral treatment. Therefore, clinical trials of FNC treating COVID-19 with larger sample size are warranted.

Approved HIV reverse transcriptase inhibitors in the past decade

Acta Pharm Sin B 2022 Apr;12(4):1567-1590.PMID:35847492DOI:10.1016/j.apsb.2021.11.009.

HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, Azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.

FNC: An Advanced Anticancer Therapeutic or Just an Underdog?

Front Oncol 2022 Feb 10;12:820647.PMID:35223502DOI:10.3389/fonc.2022.820647.

Azvudine (FNC) is a novel cytidine analogue that has both antiviral and anticancer activities. This minireview focuses on its underlying molecular mechanisms of suppressing viral life cycle and cancer cell growth and discusses applications of this nucleoside drug for advanced therapy of tumors and malignant blood diseases. FNC inhibits positive-stand RNA viruses, like HCV, EV, SARS-COV-2, HBV, and retroviruses, including HIV, by suppressing their RNA-dependent polymerase enzymes. It may also inhibit such enzyme (reverse transcriptase) in the human retrotransposons, including human endogenous retroviruses (HERVs). As the activation of retrotransposons can be the major factor of ongoing cancer genome instability and consequently higher aggressiveness of tumors, FNC has a potential to increase the efficacy of multiple anticancer therapies. Furthermore, FNC also showed other aspects of anticancer activity by inhibiting adhesion, migration, invasion, and proliferation of malignant cells. It was also reported to be involved in cell cycle arrest and apoptosis, thereby inhibiting the progression of cancer through different pathways. To the date, the grounds of FNC effects on cancer cells are not fully understood and hence additional studies are needed for better understanding molecular mechanisms of its anticancer activities to support its medical use in oncology.

4'-Modified Nucleosides for Antiviral Drug Discovery: Achievements and Perspectives

Acc Chem Res 2022 Feb 15;55(4):565-578.PMID:35077644DOI:10.1021/acs.accounts.1c00697.

Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4'-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4'-modified nucleosides should have 3'-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3'-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4'-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4'-substituent and 3'-OH changes the furanose conformation to the 3'-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4'-modified nucleoside drug candidates such as Azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4+ T cells in HIV-1 patients receiving FNC. The 4'-azido group in Azvudine stabilizes the 3'-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3'-OH group, thus decreasing the nucleophilicity of 3'-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.