Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors

Abstract

The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 N 7-methyltransferase. These hybrid molecules showed excellent potency, high selectivity toward various human methyltransferases, nontoxicity, and high cell permeability. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase has no significant effect on virus transcription and replication at the cellular level. Therefore, our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in the viral life cycle and the pathogenesis of COVID-19.

N-Arylsulfonamide-based adenosine analogues to target RNA cap N7-methyltransferase nsp14 of SARS-CoV-2

“…5,10–14 Spurred by the recent SARS-CoV-2 pandemic, the N 7-MTase nsp14 is an emerging target of great interest for inhibitor development, and over the past three years numerous groups worldwide have proposed original active compounds against this enzyme. 15–28 Most nsp14 inhibitors have been designed as SAM-derived compounds, 17,19,21,23–26,28 but high-throughput screening of large libraries 18,20 or a structure-based docking approach on large libraries 27 have also lead to non-SAM-like inhibitors of nsp14. In the latest docking study, 27 the most potent inhibitors are low micromolar, much weaker than the most potent SAM-derived inhibitor, which is active in the subnanomolar range against SARS-CoV-2 nsp14.…”

“…23,26 N -Arylsulfonamides, known to be ubiquitous functional scaffolds among medicinally interesting molecules, proved to be here a key component in explaining the inhibitors' high affinity for SARS-CoV-2 nsp14 (tens of nanomolar inhibition) in our work 23,26,29 and that of others. 24,28 In these potent inhibitors, the N -arylsulfonamide moieties were directly attached to the C5′ ribose atom of adenosine or its derivatives (Fig. 1A).…”

Application of established computational techniques to identify potential SARS-CoV-2 Nsp14-MTase inhibitors in low data regimes

“…It is of interest to note that prior approaches targeting this protein have typically combined synthesis with docking strategies to rene and enhance the potency of existing inhibitors. 14,15 In contrast, our approach exploits the power of virtual screening across various levels of accuracy, alongside the use of the NCI open compound collection 16,17 -a database encompassing over 250 000 molecules freely available to researchers worldwide. For an overview of the property distributions within this collection, refer to Fig.…”