A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase

Khan, Suliman; Attar, Farideh; Bloukh, Samir Haj; Sharifi, Majid; Nabi, Faisal; Bai, Quan; Khan, Rizwan Hasan; Falahati, Mojtaba

doi:10.1016/j.ijbiomac.2021.03.112

Cited by 22 publications

(16 citation statements)

References 75 publications

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“…Furthermore, regardless of the differences between their binding energies and ours, the fact that the cells have higher mM [ATP] concentrations than [CTP] in vivo, because the former is the major energy currency of the cells, suggests that Lamivudine-TP must be able to compete with CTP for binding to the SARS-CoV-2 RdRp similarly, or possibly better than Remdesivir-TP competing vs. ATP for the same enzyme. In concordance with these conclusions, a recent review on the effect of ANNAs on the SARS-CoV-2 RdRp arrived at the same prediction for Lamivudine (84). Additionally, a recent docking report indicates the putative binding of Lamivudine to the main protease (MPro) of the SARS-CoV-2 (35), therefore it seems possible that, as reviewed here, Lamivudine could inhibit the three key SARS-CoV-2 processes: Spike/ACE2 interaction, processing by MPro and, as found here, RNA replication by the SARS-CoV-2 RdRp polymerase.…”

Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19supporting

confidence: 64%

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

2021

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Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

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Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19supporting

confidence: 64%

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

2021

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“…The incorporation of FNC blocks subsequent attachment of nucleotides to the 3′-hydroxy group, thus terminating the synthesis of the RNA chain and virus replication (Figure ). Additionally, nucleoside-based antivirals could suppress viral replication by inhibiting DNA- and RNA-dependent polymerases . Consequently, we speculate that clinically used nucleoside-based antivirals may have the potential to be repurposed for COVID-19 treatment.…”

Section: ′-Modified Nucleosides Used In Antiviral Therapiesmentioning

confidence: 96%

“…Additionally, nucleoside-based antivirals could suppress viral replication by inhibiting DNA-and RNAdependent polymerases. 24 Consequently, we speculate that clinically used nucleoside-based antivirals may have the potential to be repurposed for COVID-19 treatment. Encouragingly, in our preliminary randomized, open-label, controlled clinical trial (clinical trial numbers: C h i C T R 2 0 0 0 0 2 9 8 5 3 , C h i C T R 2 0 0 0 0 3 0 0 4 1 , ChiCTR2000030424, and ChiCTR2000030487), we found that azvudine shortened the mean time (2.60 days) of the first nucleic acid negative conversion (NANC) of mild and common COVID-19 patients, shorter than that (5.60 days) of those receiving standard antiviral treatment (interferon alpha, kaletra and ribavirin, chloroquine phosphate, and hydroxychloroquine sulfate).…”

Section: Azvudine (Fnc)mentioning

confidence: 98%

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

Chang

2022

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: 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 longlasting 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 perspective...

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“…The increased awareness that started in the 1960s of the therapeutic significance of modified nucleosides in the treatment of viral and bacterial infections quickly led to the syntheses of small molecules that do not destroy viral pathogens but rather inhibit their replication and transcription [28] , [29] . The study of nucleoside analogs as antiviral agents has undergone extraordinary advancements, from the original empirical viral infection inhibition with purine analogs painstakingly synthesized in the laboratory [30] , to in silico methodologies that allow the rapid identification of nucleoside analogs with potential antiviral activity by inhibiting viral replication or transcription [31] .…”

Section: Introductionmentioning

confidence: 99%

Subtle structural differences of nucleotide analogs may impact SARS-CoV-2 RNA-dependent RNA polymerase and exoribonuclease activity

Madariaga-Mazón

Naveja²,

Becerra³

et al. 2022

Computational and Structural Biotechnology Journal

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A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase

Cited by 22 publications

References 75 publications

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

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

Subtle structural differences of nucleotide analogs may impact SARS-CoV-2 RNA-dependent RNA polymerase and exoribonuclease activity

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