Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase

Abstract

Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds 3 and 10 . As a prototypic inhibitor, compound 3 also has an excellent selectivity profile over a panel of human methyltransferases. Remarkably, C -nucleoside 10 exhibits high antiviral activity and low cytotoxicity, leading to a therapeutic index (CC 50 /EC 50 ) greater than 139. Furthermore, a brief metabolic profiling of these two compounds suggests that they are less likely to suffer from major metabolic liabilities. Moreover, computational docking studies point to protein–ligand interactions that can be exploited to enhance inhibitory activity. In short, discovery of inhibitor 10 clearly demonstrates that potent and selective anti-SARS-CoV-2 activity can be achieved by targeting the Nsp14 methyltransferase. Therefore, the current work strongly supports the continued pursuit of Nsp14 methyltransferase inhibitors as COVID-19 therapeutics.

3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors

“…SAM structure consists of amino acid moiety and adenosine. A rational design of nsp14 bisubstrate inhibitors was reported, where methionine was substituted with various N -alkyl-benzenesulfonamides to target both SAM and RNA substrate-binding pockets ( 1a , Figure 1 ) [ 17 , 18 , 19 ]. Other research groups focused on substituted 7-deazaadenosine derivatives resulting in nanomolar nsp14 inhibitors 1b [ 20 , 21 ].…”

Facile access to 4′-(N-acylsulfonamide) modified nucleosides and evaluation of their inhibitory activity against SARS-CoV-2 RNA cap N7-guanine-methyltransferase nsp14

“…Closely related nsp14 inhibitors derived from naphtalene and benzopyridine 5′-N-sulfonamide adenosines were also recently described. 21 Considering the various benefits of the N-acylsulfonamide moiety, here we investigated how replacing the sulfonamide by an N-acylsulfonamide would modulate the biological properties of these inhibitors. Traditionally, N-acylsulfonamide derivatives are synthesized by direct acylation of the corresponding sulfonamide.…”

“…Closely related nsp14 inhibitors derived from naphtalene and benzopyridine 5′- N -sulfonamide adenosines were also recently described. 21…”

Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies

“…However, its ready-to-use format makes it better suited for industrial applications. The precoated PAMPA has especially found applications in medicinal chemistry projects [ 49 , 50 , 51 , 52 ], even including protein testing [ 53 ]. Furthermore, the precoated PAMPA has been used to determine the pH-dependent solubility and permeability profiles of >20 compounds [ 54 ] and it was used to calibrate an in silico molecular dynamics simulation method to study permeability.…”