5′-cap RNA/SAM mimetic conjugates as bisubstrate inhibitors of viral RNA cap 2′-O-methyltransferases.

5′-cap RNA/SAM mimetic conjugates as bisubstrate inhibitors of viral RNA cap 2′-O-methyltransferases.

Publication date: Feb 01, 2024

Viral RNA cap 2′-O-methyltransferases are considered promising therapeutic targets for antiviral treatments, as they play a key role in the formation of viral RNA cap-1 structures to escape the host immune system. A better understanding of how they interact with their natural substrates (RNA and the methyl donor SAM) would enable the rational development of potent inhibitors. However, as few structures of 2′-O-MTases in complex with RNA have been described, little is known about substrate recognition by these MTases. For this, chemical tools mimicking the state in which the cap RNA substrate and SAM cofactor are bound in the enzyme’s catalytic pocket may prove useful. In this work, we designed and synthesized over 30 RNA conjugates that contain a short oligoribonucleotide (ORN with 4 or 6 nucleotides) with the first nucleotide 2′-O-attached to an adenosine by linkers of different lengths and containing S or N-heteroatoms, or a 1,2,3-triazole ring. These ORN conjugates bearing or not a cap structure at 5′-extremity mimic the methylation transition state with RNA substrate/SAM complex as bisubstrates of 2′-O-MTases. The ORN conjugates were synthesized either by the incorporation of a dinucleoside phosphoramidite during RNA elongation or by click chemistry performed on solid-phase post-RNA elongation. Their ability to inhibit the activity of the nsp16/nsp10 complex of SARS-CoV-2 and the NS5 protein of dengue and Zika viruses was assessed. Significant submicromolar IC values and K values in the uM range were found, suggesting a possible interaction of some ORN conjugates with these viral 2′-O-MTases.

Concepts Keywords
Antiviral 2′-O-methyltransferase
Host Bisubstrate
Oligoribonucleotide Cap RNA
Useful Conjugate
Viral Dengue virus
NS5 protein
Nsp16 protein
SAM analogues


Type Source Name
drug DRUGBANK Ademetionine
disease IDO host
pathway REACTOME Immune System
drug DRUGBANK Tropicamide
drug DRUGBANK Adenosine
disease VO NS5
disease MESH dengue
disease VO Viruses

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