Synthesis of Adenine Dinucleosides 2′,5′‐Bridged by Sulfur‐Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′‐<i>O</i>‐Methyltransferases

Ahmed‐Belkacem, Rostom; Sutto-Ortiz, Priscila; Decroly, Étienne; Vasseur, Jean‐Jacques; Debart, Françoise

doi:10.1002/ejoc.201901120

Cited by 5 publications

(10 citation statements)

References 36 publications

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“…The retrosynthetic analysis of the dinucleoside 1 structure suggested the coupling reaction between the tosyl derivative 17 previously described by us (Scheme 2) [14], and the readily accessible 5 0 -amino-2 0 ,3 0 -isopropylidene adenosine [21]. The direct Nalkylation at room temperature did not afford the secondary amine in satisfactory yields and when increasing the temperature to enhance the reactivity of the primary amine, we noticed degradation of 17.…”

Section: Chemistrymentioning

confidence: 65%

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Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

Ahmed‐Belkacem

Sutto-Ortiz

Guiraud

et al. 2020

European Journal of Medicinal Chemistry

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The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7-or 2 0 O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2 0-O-methylation of the cap RNA in order to block viral 2 0-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2 0-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.

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Section: Chemistrymentioning

confidence: 65%

“…1). Recently, we described the synthesis of a first series of bisubstrate adenine dinucleosides with various sulfur-containing linkers [14]. Unexpectedly, such compounds tested at 50 mM or 200 mM concentration failed to inhibit several RNA 2 0 O-MTases of SARS-CoV, Zika, West Nile, Dengue and Pox viruses such as vaccinia virus.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

Ahmed‐Belkacem

Sutto-Ortiz

Guiraud

et al. 2020

European Journal of Medicinal Chemistry

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“…[17] Among a small library of synthesized dinucleosides, dinucleoside 9 containing a 4-chloro-3-nitrobenzenesulfonamide moiety displayed the best inhibitory activity with an IC 50 of 0.6 μM (Figure 6). Thermal shift assay [15,16] Figure 6. Transition state of N7-methylation of mRNA cap structure by SAM and structure of adenine dinucleoside 9 as inhibitor of SARS-CoV N7-MTase nsp14.…”

Section: Targeting 2'o-rna Mtasesmentioning

confidence: 99%

“…[14] To overcome this lack of selectivity, our group recently reported the synthesis of bisubstrate nucleoside analogues 6-8 as potential inhibitors of 2'O-MTases by mimicking the transition state of 2'O-methylation of RNA with each substrate (Figure 5). Several dinucleosides were designed with an adenosine in place of the SAM adenosine, linked to the 2'-OH of an adenosine unit via linkers of different sizes containing various heteroatoms (S, [15] N [16] ), groups of atoms, and even the amino acid side chain of SAM.…”

Section: Targeting 2'o-rna Mtasesmentioning

confidence: 99%

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Bisubstrate Strategies to Target Methyltransferases

Ahmed‐Belkacem

Debart

2022

Eur J Org Chem

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Bisubstrate strategies address the lack of specificity encountered with S‐adenosyl‐L‐methionine (SAM) analogues targeting methyltransferases (MTases). Specifically, a bisubstrate inhibitor mimics the transition state complex associating a substrate and the SAM methyl group donor to a particular methyltransferase. These potential inhibitors contain both parts of the substrate and the methyl group donor. In this review, bisubstrate inhibitors of several MTases including DNA, RNA, protein, catechol or nicotinamide MTases are discussed in order to evaluate the interest of these promising molecules for the development of selective therapeutics against cancers, neuropsychiatric disorders and viral infections.

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Synthesis of Bisubstrate Analogues for RNA Methylation Studies using two Transition‐Metal‐Catalyzed Reactions

Coelho

Corre

Bartosik

et al. 2023

Chemistry A European J

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RNA methyltransferases (RNA MTases) are a family of enzymes that catalyze the methylation of RNA using the cofactor S‐adenosyl‐L‐methionine. While RNA MTases are promising drug targets, new molecules are needed to fully understand their roles in disease and to develop effective drugs that can modulate their activity. Since RNA MTases are suitable for bisubstrate binding, we report an original strategy for the synthesis of a new family of m6A MTases bisubstrate analogues. Six compounds containing a S‐adenosyl‐L‐methionine (SAM) analogue unit covalently tethered by a triazole ring to the N‐6 position of an adenosine were synthesized. A procedure using two transition‐metal‐catalyzed reactions was used to introduce the α‐amino acid motif mimicking the methionine chain of the cofactor SAM. First, a copper(I)‐catalyzed alkyne‐azide iodo‐cycloaddition (iCuAAC) reaction afforded the 5‐iodo‐1,4‐disubstituted‐1,2,3‐triazole which was functionalized by palladium‐catalyzed cross‐coupling to connect the α‐amino acid substituent. Docking studies of our molecules in the active site of the m6A ribosomal MTase RlmJ show that the use of triazole as a linker provides additional interactions and the presence of the α‐amino acid chain stabilizes the bisubstrate. The synthetic method developed here enhances the structural diversity of bisubstrate analogues to explore the active site of RNA modification enzymes and to develop new inhibitors.

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Synthesis of Adenine Dinucleosides 2′,5′‐Bridged by Sulfur‐Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′‐O‐Methyltransferases

Cited by 5 publications

References 36 publications

Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

Bisubstrate Strategies to Target Methyltransferases

Synthesis of Bisubstrate Analogues for RNA Methylation Studies using two Transition‐Metal‐Catalyzed Reactions

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