A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

Ohrui, Hiroshi

doi:10.4172/jaa.1000092

Cited by 5 publications

(2 citation statements)

References 36 publications

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“…4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA, 1 ) is a nucleoside reverse transcriptase inhibitor (NRTI) created by collaborative studies among the Ohrui group, Mitsuya group, and Yamasa Corp. (Figure ) . The structure of 1 differs substantially from other NRTIs clinically approved for the treatment of human immunodeficiency virus (HIV) infection, since it retains the 3′-OH functionality of 2′-deoxyadenosine as well as the presence of the 2-fluoro substituent .…”

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confidence: 99%

Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

2015

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An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-D-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4' position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2'-deoxygenation of a ribonucleoside intermediate.

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Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

2015

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“…MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine), a novel nucleoside analog that possesses a 3′-hydroxyl group, is more potent against wild-type and most clinical drug-resistant HIV strains than any approved nucleoside reverse transcriptase inhibitor (NRTI) . Unlike other NRTIs and due to its unique structure bearing a 4′-ethynyl substituent and a 3′-hydroxy group (Chart ), MK-8591 has been shown to display multiple novel modes of action, acting in part as a translocation-defective RT inhibitor (NRTTI) .…”

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confidence: 99%

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

Alexandre¹,

Rahali²,

Rahali³

et al. 2018

J. Med. Chem.

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MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4′-Ethynyl-G derivative (±)-29 displayed a promising IC 50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC 50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC 50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.

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Intriguing Antiviral Modified Nucleosides: A Retrospective View into the Future Treatment of COVID-19

Ami

Ohrui

2021

ACS Med. Chem. Lett.

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Great pioneers of nucleic acid chemistry had elucidated nucleic acid functions and structures and developed various antiviral modified nucleoside drugs. It is possible in theory that antiviral modified nucleosides prevent viral replication by inhibiting viral polymerases. However, biological phenomena far exceed our predictions at times. We describe the characteristics of the approved antiviral modified nucleosides from an organic chemistry perspective. Also, based on our experiences and findings through the development of the HIV-1 reverse-transcriptase inhibitor “Islatravir”, we provide the practical and approximate guidelines for the drug development of antiviral modified nucleosides against COVID-19.

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A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

Cited by 5 publications

References 36 publications

Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

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

Intriguing Antiviral Modified Nucleosides: A Retrospective View into the Future Treatment of COVID-19

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