Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses

Abstract

Noroviruses belong to the Caliciviridae family of single-stranded positive-sense RNA viruses. The genus Norovirus includes seven genogroups (designated GI-GVII), of which GI, GII and GIV infect humans. Human noroviruses are responsible for widespread outbreaks of acute gastroenteritis and represent one of the most common causes of foodborne illness. No vaccine or antiviral treatment options are available for norovirus infection. The RNA-dependent RNA polymerase (RdRp) of noroviruses is a key enzyme responsible for transcription and replication of the viral genome. Here, we review the progress made in understanding the structures and functions of norovirus RdRp and its use as a target for small molecule inhibitors. Crystal structures of the RdRp at different stages of substrate interaction have been determined, which shed light on its multi-step catalytic cycle. The in vitro assays and in vivo animal models that have been developed to identify and characterize inhibitors of norovirus RdRp are also summarized, followed by an update on the current antiviral research targeting different regions of norovirus RdRp. In the future, structure-based drug design and rational optimization of known nucleoside and non-nucleoside inhibitors of norovirus RdRp may pave the way towards the next generation of direct-acting antivirals.

Genetic and Epidemiologic Trends of Norovirus Outbreaks in the United States from 2013 to 2016 Demonstrated Emergence of Novel GII.4 Recombinant Viruses

“…High error rates among low-fidelity RNA polymerases drive intrahost diversity, a feature important for viral fitness, evolution, and pathogenesis (57). There is evidence that epidemic GII.4 variants have historically evolved through both antigenic drift and recombination at the ORF1-ORF2 junction, resulting in acquisition of a new polymerase (21,25).…”

First detection of neboviruses in yak (Bos grunniens) and identification of a novel neboviruses based on complete genome

“…Until now, the precise functions of NeVs RdRp has not been reported. However, RdRp of the other caliciviruses plays a critical role in the replication (Deval et al, 2016;Lee et al, 2017). The rotation of the central helix in the thumb domain and displacement of the C-terminal tail at the active site are essential to bind RNA and substrates (Lee et al, 2017).…”

“…In this study, strains YAK/NRG17/17/CH and YAK/HY1-2/18/ CH share 8 identical amino acid variations in the C-terminal region (35 amino acid), compared with other all six available complete RdRp, which may have influence the virus replication of the novel NeVs strain. RdRp-driven genetic diversity is vital for viral fitness (Deval et al, 2016). In pandemic noroviruses strain, the RdRp displays reduced replication fidelity, which results in higher mutation rate and rate of viral evolution compared to the non-pandemic and less frequently detected strains (Bull et al, 2010).…”

“…Moreover, the VP1 of other caliciviruses has been identified to be involved in host specificity and immunogenicity (Chen et al, 2006;Smith et al, 2019;Song et al, 2017). Although the precise functions of NeVs RdRp has not been determined, the RdRp of other caliciviruses is a key enzyme responsible for transcription, replication of the viral genome and accurate initiation of RNA synthesis (Deval et al, 2016;Lee et al, 2017).…”

Norovirus GII.P16/GII.2 Strain in Shenzhen, China: A Retrospective Study

“…Pro cleaves the polyprotein translated from ORF1 [10]. The RNA-dependent RNA polymerase (RdRp) of norovirus is a key enzyme which responsible for transcription and replication of the viral genome [11]. These proteins are important for replication of NoV. ORF2 is 1.6 kb and encodes major structural protein VP1, which composes main capsid structure and responsible for infectivity and antigenicity of NoV [12].…”