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Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens.

ABSTRACT: Human noroviruses are the leading causative agents of epidemic and sporadic viral gastroenteritis and childhood diarrhoea worldwide. Human histo-blood group antigens (HBGA) serve as receptors for norovirus capsid protein attachment and play a critical role in infection. This makes HBGA-norovirus binding a promising target for drug development. Recently solved crystal structures of norovirus bound to HBGA have provided a structural basis for identification of potential anti-norovirus drugs and subsequently performed in silico and in vitro drug screens have identified compounds that block norovirus binding and may thereby serve as structural templates for design of therapeutic norovirus inhibitors. This review explores norovirus therapeutic options based on the strategy of blocking norovirus-HBGA binding.

SUBMITTER: Ali ES

PROVIDER: S-EPMC5026924 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens.

Ali Eunüs S ES Rajapaksha Harinda H Carr Jillian M JM Petrovsky Nikolai N

Antiviral research 20160713

Human noroviruses are the leading causative agents of epidemic and sporadic viral gastroenteritis and childhood diarrhoea worldwide. Human histo-blood group antigens (HBGA) serve as receptors for norovirus capsid protein attachment and play a critical role in infection. This makes HBGA-norovirus binding a promising target for drug development. Recently solved crystal structures of norovirus bound to HBGA have provided a structural basis for identification of potential anti-norovirus drugs and su ...[more]

PMID: 27421712

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Project description:Human norovirus (HuNoV) is the major agent for viral gastroenteritis, causing >700 million infections yearly. Fucose-containing carbohydrates named histo-blood group antigens (HBGAs) are known (co)receptors for HuNoV. Moreover, bacteria of the gut microbiota expressing HBGA-like structures have shown an enhancing effect on HuNoV replication in an in vitro model. Here, we studied the role of HBGAs and the host microbiota during HuNoV infection in zebrafish larvae. Using whole-mount immunohistochemistry, we visualized the fucose expression in the zebrafish gut for the HBGA Lewis X [LeX, α(1,3)-fucose] and core fucose [α(1,6)-fucose]. Costaining of HuNoV-infected larvae proved colocalization of LeX and to a lower extent core fucose with the viral capsid protein VP1, indicating the presence of fucose residues on infected cells. Upon blocking of fucose expression by a fluorinated fucose analogue, HuNoV replication was strongly reduced. Furthermore, by comparing HuNoV replication in conventional and germfree zebrafish larvae, we found that the natural zebrafish microbiome does not have an effect on HuNoV replication, contrary to earlier reports about the human gut microbiome. Interestingly, monoassociation with the HBGA-expressing Enterobacter cloacae resulted in a minor decrease in HuNoV replication, which was not triggered by a stronger innate immune response. Overall, we show here that fucose has an essential role for HuNoV infection in zebrafish larvae, as in the human host, but their natural gut microbiome does not affect viral replication. IMPORTANCE Despite causing over 700 million infections yearly, many gaps remain in the knowledge of human norovirus (HuNoV) biology due to an historical lack of efficient cultivation systems. Fucose-containing carbohydrate structures, named histo-blood group antigens, are known to be important (co)receptors for viral entry in humans, while the natural gut microbiota is suggested to enhance viral replication. This study shows a conserved mechanism of entry for HuNoV in the novel zebrafish infection model, highlighting the pivotal opportunity this model represents to study entry mechanisms and identify the cellular receptor of HuNoV. Our results shed light on the interaction of HuNoV with the zebrafish microbiota, contributing to the understanding of the interplay between gut microbiota and enteric viruses. The ease of generating germfree animals that can be colonized with human gut bacteria is an additional advantage of using zebrafish larvae in virology. This small animal model constitutes an innovative alternative to high-severity animal models.

Dataset Information

Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens.

Publications

Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens.

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