Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4′-Ethynyl-2-fluoro-2′-deoxyadenosine)

Alexandre, François-René; Rahali, Rachid; Rahali, Houcine; Guillon, Sandra; Convard, Thierry; Fillgrove, Kerry L.; Lai, Ming‐Tain; Meillon, Jean‐Christophe; Xu, Min; Small, James H.; Dousson, Cyril B.; Raheem, Izzat T.

doi:10.1021/acs.jmedchem.8b00141

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…Recently, Maeda et al reported that 4′-ethynyl was the key structural feature for the potency against drug-resistant HIV-1 strains . Replacing the ribose sugar ring in islatravir with a carbocycle gave carbocyclic nucleoside analogs with promising anti-HIV-1 activity and IC 50 values reaching 3.0 nM (Figure A) . Compared to their ribose counterparts, the carbocyclic analogs are more stable toward glycosidases and have improved pharmacokinetic profiles.…”

Section: ′-Modified Nucleosides Used In Antiviral Therapiesmentioning

confidence: 99%

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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Section: ′-Modified Nucleosides Used In Antiviral Therapiesmentioning

confidence: 99%

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

Chang

2022

Acc. Chem. Res.

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“…MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine, EFdA) is a novel nucleoside analogue that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved nucleoside reverse transcriptase inhibitors (NRTI) (Alexandre et al, 2018). Reverse transcriptase can use EFdA-5′triphosphate (EFdA-TP, MK-8591-TP) as a substrate more efficiently than the natural substrate, dATP (Acosta-Hoyos and Scott, 2010).…”

Section: Long Acting Antiretrovirals Dr Howard Gendelman Universitmentioning

confidence: 99%

Meeting report: 32nd International Conference on Antiviral Research

et al. 2019

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“…Several examples [ 14 , 15 , 16 ], including approved drugs entecavir and abacavir, show that this type of modification does not impact the cellular processing of the nucleoside while making compounds more resistant to nucleoside phosphorylase responsible of the N -glycosidic bond cleavage [ 17 ]. Indeed, 4′-methyl analogs ( 7 ) [ 18 ] were shown to display weak activities against a panel of RNA viruses including yellow fever (YF), dengue virus (DENV), venezuelan equine encephalis virus (VEE) and west nile virus (WNV), while 4′-ethynyl and 4′-cyano carbocyclic-2′-deoxyribonucleoside analogs ( 8a ) and ( 8b ) ( Figure 2 ) displayed anti-HIV-1 activity [ 19 ] ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4′-Substituted Carbocyclic Uracil Derivatives and Their Monophosphate Prodrugs as Potential Antiviral Agents

Biteau

Amichai

Azadi

et al. 2023

Viruses

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Over the past decades, both 4′-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4′-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A/B viruses and norovirus.

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Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4′-Ethynyl-2-fluoro-2′-deoxyadenosine)

Cited by 11 publications

References 35 publications

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

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

Meeting report: 32nd International Conference on Antiviral Research

Synthesis of 4′-Substituted Carbocyclic Uracil Derivatives and Their Monophosphate Prodrugs as Potential Antiviral Agents

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