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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10607 - Virology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

ACS Infectious Diseases

ISSN

2373-8227

e-ISSN

—

Volume of the periodical

11

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

3364-3376

UT code for WoS article

001604943600001

EID of the result in the Scopus database

2-s2.0-105021877286