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preLekára.sk / Odborné časopisy / PLOS Pathogens / 2015 - 3

The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family

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Virus replication relies on multiplication of viral genomes by viral polymerases. For enteroviruses, a large group of clinically important human pathogens for which no antiviral therapy is available, this function is performed by 3Dpol, the RNA-dependent RNA polymerase. 3Dpol is therefore an attractive target for novel antiviral strategies. Most polymerase inhibitors identified today are nucleoside analogs, a class of compounds that exert broad-spectrum activity but often suffer from off-target effects. Non-nucleoside inhibitors on the other hand, in general have a more narrow spectrum of activity and are more prone to resistance development because in most cases they bind the surface of the enzyme which is less conserved and structurally more flexible. In this study, we present the identification of GPC-N114 as a non-nucleoside inhibitor of 3Dpol with broad-spectrum antiviral activity against both enteroviruses and cardioviruses, which also belong to the picornavirus family. Remarkably, it acts by targeting the RNA template-primer binding site in the core of 3Dpol, making GPC-N114 the first anti-picornaviral compound with this mechanism of action. Thus, the characterization of GPC-N114 has led to the identification of a novel drug-binding pocket in 3Dpol that can serve as a starting point for antiviral drug design.

Vyšlo v časopise: The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004733
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004733

Souhrn

Virus replication relies on multiplication of viral genomes by viral polymerases. For enteroviruses, a large group of clinically important human pathogens for which no antiviral therapy is available, this function is performed by 3Dpol, the RNA-dependent RNA polymerase. 3Dpol is therefore an attractive target for novel antiviral strategies. Most polymerase inhibitors identified today are nucleoside analogs, a class of compounds that exert broad-spectrum activity but often suffer from off-target effects. Non-nucleoside inhibitors on the other hand, in general have a more narrow spectrum of activity and are more prone to resistance development because in most cases they bind the surface of the enzyme which is less conserved and structurally more flexible. In this study, we present the identification of GPC-N114 as a non-nucleoside inhibitor of 3Dpol with broad-spectrum antiviral activity against both enteroviruses and cardioviruses, which also belong to the picornavirus family. Remarkably, it acts by targeting the RNA template-primer binding site in the core of 3Dpol, making GPC-N114 the first anti-picornaviral compound with this mechanism of action. Thus, the characterization of GPC-N114 has led to the identification of a novel drug-binding pocket in 3Dpol that can serve as a starting point for antiviral drug design.

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Článek Transgenic Expression of the Dicotyledonous Pattern Recognition Receptor EFR in Rice Leads to Ligand-Dependent Activation of Defense Responses
Článek Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer
Článek Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
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PLOS Pathogens

2015 Číslo 3
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Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
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