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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00574244" target="_blank" >RIV/61388963:_____/23:00574244 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/23:10467206 RIV/60461373:22330/23:43926872

Výsledek na webu

<a href="https://doi.org/10.1021/acsomega.3c02815" target="_blank" >https://doi.org/10.1021/acsomega.3c02815</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsomega.3c02815" target="_blank" >10.1021/acsomega.3c02815</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 N7-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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 N7-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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10607 - Virology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Omega

ISSN

2470-1343

e-ISSN

2470-1343

Svazek periodika

8

Číslo periodika v rámci svazku

30

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

27410-27418

Kód UT WoS článku

001031748300001

EID výsledku v databázi Scopus

2-s2.0-85166762149