Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors

Zhang, Lina; Wei, Fenju; Borrego, David; Zhao, Fabao; Río, Javier Martínez del; Frutos-Beltrán, Estrella; Zhang, Jiwei; Xu, Shujing; López-Carrobles, Nerea; Gao, Shenghua; Kang, Dongwei; Pannecouque, Christophe; Clercq, Erik De; Liu, Xinyong; Menéndez‐Arias, Luis; Zhan, Peng

doi:10.1016/j.ejmech.2022.114563

Cited by 4 publications

(6 citation statements)

References 56 publications

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“…The natural product BTP (2,7-dihydroxy-4-isopropyl-cyclohepta-2,4,6,-triene or β-thujaplicinol, isolated from Thuja plicata ) and various synthetic heterocyclic compounds were reported to possess similar nanomolar activity against HIV-1 RNase H [ 27 , 59 , 60 ]. Only a recently disclosed winged N -galloyl- N -sulfonylpiperazine-based HIV-1 RNase H inhibitor showed a higher activity [ 61 ]. In contrast, a 6-nitro-7,8-dihydroxycoumarin derivative exhibited distinctly lower HIV-1 RNase H inhibition than 1c [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

Asthana

Corona

Shin

et al. 2023

Viruses

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Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3′-to-5′ exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

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Section: Discussionmentioning

confidence: 99%

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

Asthana

Corona

Shin

et al. 2023

Viruses

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“…In this study, we evaluated RdRp binding activity of an in-house compound library containing metal ion chelators with piperazine scaffold (over 100 compounds of polyphenol, 1-hydroxy-1,8-naphthyridinone, 5-hydroxypyrido [2,3-b]pyrazinone, and 4-hydroxyquinazolinone analogues, originally designed and synthesized for anti-HIV-1, see Supplementary Material) [32][33][34][35][36] screened by established high-throughput enzyme assays of RdRp complex, as novel antiviral therapeutic candidates for COVID-19 through target activity verification and cell-based activity evaluation. A polymerase reaction system was built to evaluate the residual activity of RdRp in the presence of inhibitors [37,38].…”

Section: In-house Library Screening For Potent Rdrp Inhibitorsmentioning

confidence: 99%

“…All the compounds were synthesized and published by our laboratory as racemic mixtures [32][33][34][35][36]. Each compound was prepared as a 10 mM stock solution with dimethyl sulfoxide (DMSO, Sigma Aldrich, Belgium) and then stored at −20 °C .…”

Section: Compounds and The Stock Solutionmentioning

confidence: 99%

Identification of Polyphenol Derivatives as Novel SARS-CoV-2 and DENV Non-Nucleoside RdRp Inhibitors

Gao

Song

et al. 2022

Molecules

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The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47/DF-51 and SARS-CoV-2/DENV RdRp, respectively, including chelating with Mg2+ near polymerase active site. This work discovered the inhibitory effect of two polyphenols on distinct viral RdRp, which are expected to be developed into broad-spectrum, non-nucleoside RdRp inhibitors with new scaffold.

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“…Many RNase H inhibitors have been designed to bind to the catalytic center, interacting with divalent metal ions . Several scaffolds have been reported as RNase H inhibitors, including diketo acids, pyrimidinol, naphthyridine, and naphthyridine derivatives as well as galloyl derivatives . In these compounds, oxygen atoms of a carbonyl or hydroxy group are aligned in a row and chelated to the two divalent metals.…”

mentioning

confidence: 99%

“…6 T h i s c o n t e n t i s Several scaffolds have been reported as RNase H inhibitors, 7 including diketo acids, 8 pyrimidinol, 9 naphthyridine, and naphthyridine derivatives 10 as well as galloyl derivatives. 11 In these compounds, oxygen atoms of a carbonyl or hydroxy group are aligned in a row and chelated to the two divalent metals. Compounds bearing a 5-nitro-furan-2-carboxylic acid ester scaffold were also found to suppress HIV-1 RT-associated RNase H activity.…”

mentioning

confidence: 99%

Sticklac-Derived Natural Compounds Inhibiting RNase H Activity of HIV-1 Reverse Transcriptase

Ito,

Lu,

Kitajima

et al. 2023

J. Nat. Prod.

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The emergence of drug-resistant viruses is a serious concern in current chemotherapy for human immunodeficiency virus type-1 (HIV-1) infectious diseases. Hence, antiviral drugs aiming at targets that are different from those of approved drugs are still required, and the RNase H activity of HIV-1 reverse transcriptase is a suitable target. In this study, a search of a series of natural compounds was performed to identify the RNase H inhibitors. Three compounds were found to block the RNase H enzymatic activity. A laccaic acid skeleton was observed in all three natural compounds. A hydroxy phenyl group is connected to an anthraquinone backbone in the skeleton. An acetamido-ethyl, amino-carboxy-ethyl, and amino-ethyl are bound to the phenyl in laccaic acids A, C, and E, respectively. Laccaic acid C showed a 50% inhibitory concentration at 8.1 μM. Laccaic acid C also showed inhibitory activity in a cell-based viral proliferation assay. Binding structures of these three laccaic acids were determined by X-ray crystallographic analysis using a recombinant protein composed of the HIV-1 RNase H domain. Two divalent metal ions were located at the catalytic center in which one carbonyl and two hydroxy groups on the anthraquinone backbone chelated two metal ions. Molecular dynamics simulations were performed to examine the stabilities of the binding structures. Laccaic acid C showed the strongest binding to the catalytic site. These findings will be helpful for the design of potent inhibitors with modification of laccaic acids to enhance the binding affinity.

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Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors

Cited by 4 publications

References 56 publications

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

Identification of Polyphenol Derivatives as Novel SARS-CoV-2 and DENV Non-Nucleoside RdRp Inhibitors

Sticklac-Derived Natural Compounds Inhibiting RNase H Activity of HIV-1 Reverse Transcriptase

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