A guanidine-based coronavirus replication inhibitor which targets the nsp15 endoribonuclease and selects for interferon-susceptible mutant viruses DOI Creative Commons
Benjamin Van Loy, Eugènia Pujol, Kenichi Kamata

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012571 - e1012571

Published: Feb. 11, 2025

The approval of COVID-19 vaccines and antiviral drugs has been crucial to end the global health crisis caused by SARS-CoV-2. However, prepare for future outbreaks from drug-resistant variants novel zoonotic coronaviruses (CoVs), additional therapeutics with a distinct mechanism are needed. Here, we report guanidine-substituted diphenylurea compound that suppresses CoV replication interfering uridine-specific endoribonuclease (EndoU) activity viral non-structural protein-15 (nsp15). This compound, designated EPB-113, exhibits strong selective cell culture against human coronavirus 229E (HCoV-229E) also Viruses, selected under EPB-113 pressure, carried resistance sites at or near catalytic His250 residue nsp15-EndoU domain. Although best-known function EndoU is avoid induction type I interferon (IFN-I) lowering levels dsRNA, was found mainly act via an IFN-independent mechanism, situated during RNA synthesis. Using combination biophysical enzymatic assays recombinant nsp15 proteins HCoV-229E SARS-CoV-2, discovered enhances cleavage hexameric nsp15, while reducing its thermal stability. explains why virus escapes acquiring site mutations which impair binding abolish activity. Since EPB-113-resistant mutant viruses induce high IFN-I effectors, they proved unable replicate in macrophages were readily outcompeted wild-type upon co-infection fibroblast cells. Our findings suggest targeting can be achieved molecule induces conformational change this protein, resulting higher impairment Based on appealing profile conclude challenging but highly relevant drug target.

Language: Английский

A guanidine-based coronavirus replication inhibitor which targets the nsp15 endoribonuclease and selects for interferon-susceptible mutant viruses DOI Creative Commons
Benjamin Van Loy, Eugènia Pujol, Kenichi Kamata

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012571 - e1012571

Published: Feb. 11, 2025

The approval of COVID-19 vaccines and antiviral drugs has been crucial to end the global health crisis caused by SARS-CoV-2. However, prepare for future outbreaks from drug-resistant variants novel zoonotic coronaviruses (CoVs), additional therapeutics with a distinct mechanism are needed. Here, we report guanidine-substituted diphenylurea compound that suppresses CoV replication interfering uridine-specific endoribonuclease (EndoU) activity viral non-structural protein-15 (nsp15). This compound, designated EPB-113, exhibits strong selective cell culture against human coronavirus 229E (HCoV-229E) also Viruses, selected under EPB-113 pressure, carried resistance sites at or near catalytic His250 residue nsp15-EndoU domain. Although best-known function EndoU is avoid induction type I interferon (IFN-I) lowering levels dsRNA, was found mainly act via an IFN-independent mechanism, situated during RNA synthesis. Using combination biophysical enzymatic assays recombinant nsp15 proteins HCoV-229E SARS-CoV-2, discovered enhances cleavage hexameric nsp15, while reducing its thermal stability. explains why virus escapes acquiring site mutations which impair binding abolish activity. Since EPB-113-resistant mutant viruses induce high IFN-I effectors, they proved unable replicate in macrophages were readily outcompeted wild-type upon co-infection fibroblast cells. Our findings suggest targeting can be achieved molecule induces conformational change this protein, resulting higher impairment Based on appealing profile conclude challenging but highly relevant drug target.

Language: Английский

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