Potent Activity of a Nucleoside Reverse Transcriptase Inhibitor, 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine, against Human Immunodeficiency Virus Type 1 Infection in a Model Using Human Peripheral Blood Mononuclear Cell-Transplanted NOD/SCID Janus Kinase 3 Knockout Mice

Hattori, Shin-ichiro; Ide, Kazuhiko; Nakata, Hirotomo; Harada, Hideki; Suzu, Shinya; Ashida, Noriyuki; Kohgo, Satoru; Hayakawa, Hisao; Mitsuya, Hiroaki; Okada, Seiji

doi:10.1128/aac.00270-09

Cited by 47 publications

(61 citation statements)

References 33 publications

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“…PBMCs with an EC 50 of 50 pM (Table 2), consistent with previously published data obtained using T-cell lines (12,13), and data published after completion of this work (23). The antiviral potency of EFdA is at least 4 orders of magnitude greater than the clinically used adenine nucleotide analog tenofovir and over 400-fold greater than that of AZT when assessed under the same conditions (Table 2).…”

Section: Efda-tp Is a Highly Potent Inhibitor Of Hiv-1 Rt-efda Inhibisupporting

confidence: 88%

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Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

Michailidis

Marchand

Kodama

et al. 2009

Journal of Biological Chemistry

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116

173

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Nucleoside reverse transcriptase inhibitors (NRTIs) are employed in first line therapies for the treatment of human immunodeficiency virus (HIV) infection. They generally lack a 3-hydroxyl group, and thus when incorporated into the nascent DNA they prevent further elongation. In this report we show that 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA), a nucleoside analog that retains a 3-hydroxyl moiety, inhibited HIV-1 replication in activated peripheral blood mononuclear cells with an EC 50 of 0.05 nM, a potency several orders of magnitude better than any of the current clinically used NRTIs. This exceptional antiviral activity stems in part from a mechanism of action that is different from approved NRTIs. Reverse transcriptase (RT) can use EFdA-5-triphosphate (EFdA-TP) as a substrate more efficiently than the natural substrate, dATP. Importantly, despite the presence of a 3-hydroxyl, the incorporated EFdA monophosphate (EFdA-MP) acted mainly as a de facto terminator of further RT-catalyzed DNA synthesis because of the difficulty of RT translocation on the nucleic acid primer possessing 3-terminal EFdA-MP. EFdA-TP is thus a translocation-defective RT inhibitor (TDRTI). This diminished translocation kept the primer 3-terminal EFdA-MP ideally located to undergo phosphorolytic excision. However, net phosphorolysis was not substantially increased, because of the apparently facile reincorporation of the newly excised EFdA-TP. Our molecular modeling studies suggest that the 4-ethynyl fits into a hydrophobic pocket defined by RT residues Ala-114, Tyr-115, Phe-160, and Met-184 and the aliphatic chain of Asp-185. These interactions, which contribute to both enhanced RT utilization of EFdA-TP and difficulty in the translocation of 3-terminal EFdA-MP primers, underlie the mechanism of action of this potent antiviral nucleoside.Nucleoside reverse transcriptase inhibitors (NRTIs) 4 are central components of first line regimens for treatment of HIV infections (1-6). Currently, there are eight clinically approved NRTIs: AZT, 3TC, FTC, ABC, ddI, ddC, d4T, and the nucleotide tenofovir (TFV; reviewed in Refs. 7 and 8). A structural hallmark of these NRTIs is the lack of a 3Ј-OH; it has long been considered that the absence of the 3Ј-OH is essential for antiviral activity. However, the absence of the 3Ј-OH in NRTIs also imparts detrimental properties to the inhibitor, including reduced affinity for RT compared with the analogous dNTP substrate, as well as reduced intracellular conversion to the active nucleoside triphosphate (9).Previously we described a series of 4Ј-substituted NRTIs (10) that retain the 3Ј-OH group and have excellent antiviral properties and significantly improved selectivity indices (CC 50 / EC 50 ) compared with the approved NRTIs. Furthermore, these NRTIs efficiently suppress various NRTI-resistant HIV. The most potent of these 4Ј-substituted NRTIs are the adenosine analogs that have an ethynyl group at the 4Ј position of the ribose ring. Despite their high anti-HIV activity, 4Ј-substituted compounds are susce...

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Section: Efda-tp Is a Highly Potent Inhibitor Of Hiv-1 Rt-efda Inhibisupporting

confidence: 88%

“…23), consistent with the inhibitory data obtained in transformed T-cell lines (13). The molecular basis for this exceptional antiviral activity of EFdA has to date been unclear.…”

supporting

confidence: 85%

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

Michailidis

Marchand

Kodama

et al. 2009

Journal of Biological Chemistry

Self Cite

116

173

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“…This property is attributable to the fluorine at the 2 position of the adenine base, which renders the compound resistant to degradation by adenosine deaminase (13,14). MK-8591 suppresses HIV-1 and simian immunodeficiency virus (SIV) replication at clinically achievable concentrations in humanized mice and rhesus macaques, respectively (16,(19)(20)(21). In a phase 1b proofof-concept clinical trial, a single 10-mg dose of MK-8591 demonstrated antiviral activity for 10 days in ART-naive, HIV-1-infected participants (22).…”

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confidence: 99%

“…Although MK-8591 has been shown to potently inhibit HIV-1 and SIV in culture (12)(13)(14)(15)(16)19) and in experimentally infected nonhuman primates and humanized mouse models (16,(19)(20)(21), efforts to evaluate the activity of the drug against HIV-2 are limited; a single report showed that a group B strain (HIV-2 EHO ) is sensitive to the drug in spreading infections of MT-4 cells (14). In addition, the ability of MK-8591 to inhibit HIV-2 mutants that are resistant to other NRTIs is unknown.…”

mentioning

confidence: 99%

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Smith

Masoum

et al. 2017

Antimicrob Agents Chemother

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There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4=-ethynyl-2-fluoro-2=-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC 50 ] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC 50 Յ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.

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“…It has been known that the adenine derivatives having a halogen atom at the 2-position of the base are stable to adenosine deaminase [27,28]. Therefore, 4'-C-ethynyl-2'-deoxy-2-fluoroadenosine [4'Ed2FA which was later abbreviated as EFdA [29], the structure of EFdA is shown in Table 6, therefore, EFdA is used in this paper], was synthesized and evaluated for the stability to both Anti-HIV activity was determined with MAGI assay, ND: not determined.…”

Section: Anti-hiv Activity Of 4'eda Derivatives Stable To Adenosine Dmentioning

confidence: 99%

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

Ohrui¹

2014

J Antivir Antiretrovir

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Potent Activity of a Nucleoside Reverse Transcriptase Inhibitor, 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine, against Human Immunodeficiency Virus Type 1 Infection in a Model Using Human Peripheral Blood Mononuclear Cell-Transplanted NOD/SCID Janus Kinase 3 Knockout Mice

Abstract: 4-Ethynyl

Cited by 47 publications

References 33 publications

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

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

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