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Nidovirus Replication Complexes: How enzymes shape viral genomes

Project description

Insight into Nidovirus replication

Nidoviruses are a varied group of RNA viruses that include well-known coronaviruses like SARS-CoV-2, as well as the lesser-studied Arteriviridae viruses, common in animal populations. The ERC-funded NidoRep project seeks to close this knowledge gap by focusing on how Arteriviridae viruses replicate, offering the first detailed look at their unique replication machinery. This study will examine how the speed and accuracy of replication differ among nidoviruses, providing crucial insights into their evolutionary diversity. By understanding these mechanisms, NidoRep aims to inform antiviral drug development targeting these diverse viruses, ultimately advancing preparedness for future viral outbreaks with epidemic potential.

Objective

Nidoviruses are an intriguing group of +RNA viruses, whose diverse genome sizes (11-41 kb) reflect a long history of adaptation to suit specific niches. They remain mostly neglected, with the exception of the large-genome Coronaviridae (CoV) family (32 kb), which includes the notorious human pathogen SARS-CoV-2. At the other end of the size-spectrum is the small-genome Arteriviridae (ArV) family (11 kb), an understudied group of prevalent, animal-infecting pathogens. Viral replication is mediated by a suite of enzymes known as the replication transcription complex (RTC), at the core of which is the RNA-dependent RNA polymerase (RdRp) and its unique Nterminal domain, known as the NiRAN. NidoRep aims to bridge the prevalent knowledge-gap between small and large genome nidoviruses, by deciphering the specific structural and mechanistic features of the RTC that regulate genome replication across such vastly different viruses. It will be divided into three distinct objectives: Objective 1 will focus on small-genome nidoviruses, providing the first structural and functional characterization of an ArV RTC. Objective 2 will probe how RdRp speed and fidelity have been fine-tuned to accommodate the distinct and conflicting replication requirements of diverse nidoviruses. This will be achieved through the development of an innovative in vitro sequencing assay, also providing a new and robust tool for screening drugs that corrupt RNA synthesis. Objective 3 will investigate the role of the NiRAN in initiation of RNA synthesis though protein-priming, providing new insight into the functional evolution of this complex domain, while also identifying novel drug-targeting sites. NidoRep will determine how specific viral enzymes have structurally and functionally evolved to support remarkable genome diversification within a single viral order. It will expand our understanding of understudied viruses with epidemic potential, and guide drug design strategies against key viral targets.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

(opens in new window) ERC-2024-STG

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Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 1 499 779,00
Address
RUE MICHEL ANGE 3
75794 Paris
France
Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Total cost
€ 1 499 779,00

Beneficiaries (1)