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

Abstract

SARS-CoV-2 nsp14 guanine-N7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound 5p with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound 5p acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine N-methyltransferase was not improved, the discovery of phenyl-substituted analogs 5p,t may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors.

Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases

“…Our results and the various studies published in the last two years on SARS-CoV-2 nsp14 inhibitors did not reveal any significant antiviral activity, which was unexpected given the potent nanomolar to subnanomolar inhibitions obtained on the purified enzyme [ [21] , [22] , [23] , [24] , [25] ]. Several hypotheses could explain the moderate inhibition observed.…”

“…Then, with the emergence of Covid-19, many libraries were screened on SARS-CoV-2 nsp14 but the inhibition results were rather poor [ [16] , [17] , [18] , [19] , [20] ]. In contrast, rational drug design approaches lead to the identification of much more potent inhibitors active at nanomolar [ [21] , [22] , [23] , [24] , [25] ] or subnanomolar concentration [ 25 ]. All these new inhibitors are mimics of SAM/SAH and most of them have been modeled in the crystal structure of SARS-CoV nsp14, solved in the presence of SAM (PDB 5C8T ) [ 26 ].…”

Rational design of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors

“…[17][18][19][20][21] Our group's research explored possible modifications on the purine nucleobase, 22 a strategy which has recently been used by other authors. 17,23 Intriguing result were also obtained by fragment crystallography and high-throughput screening. [24][25][26][27] Here, we follow up on our nucleobase modification study of SAH analogs and we combine it with the results obtained by substitution of the amino acid part of SAH analogues.…”

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

“…[6,7] In these bisubstrates, the link between the two substrates is based on a sulfonamide function [5,6,7] or various S-containing linkers (Figure 1D). [4,8,9] Optimization of the substituents on the sulfonamide led to powerful inhibitors of SARS-CoV N7-G MTases (nsp14) (IC 50 in the subnanomolar range). [10] Notably, in the latter cases, the nucleotide substrate is mimicked by an aryl group.…”