Targeting the Rift Valley Fever Virus Polymerase: Resistance Mechanisms and Structural Insights

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00640719" target="_blank" >RIV/61388963:_____/25:00640719 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14740/25:00142614 RIV/00216208:11110/25:10505045 RIV/00216208:11310/25:10505045

Výsledek na webu

<a href="https://doi.org/10.1021/acsinfecdis.5c00832" target="_blank" >https://doi.org/10.1021/acsinfecdis.5c00832</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsinfecdis.5c00832" target="_blank" >10.1021/acsinfecdis.5c00832</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Targeting the Rift Valley Fever Virus Polymerase: Resistance Mechanisms and Structural Insights

Popis výsledku v původním jazyce

Rift Valley fever virus (RVFV) is an arbovirus from the Phenuiviridae family that can cause severe disease in humans and livestock, with outbreaks resulting in substantial economic losses. Despite the availability of attenuated vaccines for animals, there is no approved preventive or therapeutic agent for human RVFV infections. Moreover, the safety and efficacy of the current veterinary vaccines remain uncertain. The RVFV L protein, a 250 kDa polymerase, plays a key role in viral replication and transcription, containing endonuclease, RNA-dependent RNA polymerase (RdRp), and cap-binding domains. Structurally conserved across related viruses and functionally analogous to the influenza virus polymerase, the L protein is a compelling antiviral target. In our study, we screened a library of polymerase inhibitors and identified several compounds with inhibitory activity against the RVFV polymerase. We validated their effect using both live virus assays and a minigenome luciferase reporter system. Resistance mutants were generated, and key mutations conferring resistance to the inhibitors were identified and characterized. Some of these key mutations were structurally analyzed via cryo-electron microscopy, using a new structure of the apo form of wild-type RVFV L protein resolved at 3.5 Å. This structure provides critical insights into how the mutations can influence inhibitor binding and RVFV polymerase function. These findings provide insight into how these mutations may confer resistance by affecting inhibitor binding and polymerase activity.nn

Název v anglickém jazyce

Targeting the Rift Valley Fever Virus Polymerase: Resistance Mechanisms and Structural Insights

Popis výsledku anglicky

Rift Valley fever virus (RVFV) is an arbovirus from the Phenuiviridae family that can cause severe disease in humans and livestock, with outbreaks resulting in substantial economic losses. Despite the availability of attenuated vaccines for animals, there is no approved preventive or therapeutic agent for human RVFV infections. Moreover, the safety and efficacy of the current veterinary vaccines remain uncertain. The RVFV L protein, a 250 kDa polymerase, plays a key role in viral replication and transcription, containing endonuclease, RNA-dependent RNA polymerase (RdRp), and cap-binding domains. Structurally conserved across related viruses and functionally analogous to the influenza virus polymerase, the L protein is a compelling antiviral target. In our study, we screened a library of polymerase inhibitors and identified several compounds with inhibitory activity against the RVFV polymerase. We validated their effect using both live virus assays and a minigenome luciferase reporter system. Resistance mutants were generated, and key mutations conferring resistance to the inhibitors were identified and characterized. Some of these key mutations were structurally analyzed via cryo-electron microscopy, using a new structure of the apo form of wild-type RVFV L protein resolved at 3.5 Å. This structure provides critical insights into how the mutations can influence inhibitor binding and RVFV polymerase function. These findings provide insight into how these mutations may confer resistance by affecting inhibitor binding and polymerase activity.nn

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

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

ACS Infectious Diseases

ISSN

2373-8227

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

3364-3376

Kód UT WoS článku

001604943600001

EID výsledku v databázi Scopus

2-s2.0-105021877286