Norovirus Vaccines and Potential Antinorovirus Drugs: Recent Advances and Future Perspectives

Kocher, Jacob; Yuan, Lijuan

doi:10.2217/fvl.15.57

Cited by 33 publications

(27 citation statements)

References 129 publications

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“…Genogroups GI, GII, and GIV cause human acute gastroenteritis, with GII.4 variants being more prevalent and the cause of most norovirus outbreaks . There are currently no vaccines or small molecule therapeutics for the treatment or prophylaxis of norovirus infection . Targeting critical pathways in the norovirus life cycle holds promise for the discovery of norovirus therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

et al. 2019

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Human noroviruses are the primary cause of outbreaks of acute gastroenteritis worldwide. The problem is further compounded by the current lack of norovirus‐specific antivirals or vaccines. Noroviruses have a single‐stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus‐encoded 3C‐like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication, consequently, NV 3CLpro has emerged as an attractive target for the discovery of norovirus therapeutics and prophylactics. We have recently described the structure‐based design of macrocyclic transition state inhibitors of NV 3CLpro. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors were synthesized and high resolution cocrystal structures determined. The results of our studies tentatively suggest that the macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross‐talk between the S2 and S4 subsites.

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Section: Introductionmentioning

confidence: 99%

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

et al. 2019

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“…The problem is further exacerbated by the current lack of diagnostics and norovirus-specific therapeutics and prophylactics, or vaccines. Thus, there is an urgent and unmet medical need for the discovery and development of anti-norovirus small-molecule therapeutics and prophylactics [11–14], as well as effective vaccines [15–16]. …”

Section: Introductionmentioning

confidence: 99%

Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

Kankanamalage

Kim

Rathnayake

et al. 2017

European Journal of Medicinal Chemistry

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Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.

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“…However, due to the lack of a robust culturing system and a suitable small-animal model, HuNoVs vaccine development and antiviral research have long been hampered. Promising vaccines have focused on recombinant capsid proteins, including VLPs and P particles (Kocher and Yuan, 2015). Appropriate animal models are essential tools to facilitate investigation of vaccine candidates and therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

High Protective Efficacy of Probiotics and Rice Bran against Human Norovirus Infection and Diarrhea in Gnotobiotic Pigs

et al. 2016

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Probiotics have been recognized as vaccine adjuvants and therapeutic agents to treat acute gastroenteritis in children. We previously showed that rice bran (RB) reduced human rotavirus diarrhea in gnotobiotic pigs. Human noroviruses (HuNoVs) are the major pathogens causing non-bacterial acute gastroenteritis worldwide. In this study, Lactobacillus rhamnosus GG (LGG) and Escherichia coli Nissle 1917 (EcN) were first screened for their ability to bind HuNoV P particles and virions derived from clinical samples containing HuNoV genotype GII.3 and GII.4, then the effects of LGG+EcN and RB on HuNoV infection and diarrhea were investigated using the gnotobiotic pig model. While LGG+EcN colonization inhibited HuNoV shedding, probiotic cocktail regimens in which RB feeding started 7 days prior to or 1 day after viral inoculation in the LGG+EcN colonized gnotobiotic pigs exhibited high protection against HuNoV diarrhea and shedding, characterized by significantly reduced incidence (89 versus 20%) and shorter mean duration of diarrhea (2.2 versus 0.2 days), as well as shorter mean duration of virus shedding (3.2 versus 1.0 days). In both probiotic cocktail groups, the diarrhea reduction rates were 78% compared with the control group, and diarrhea severity was reduced as demonstrated by the significantly lower cumulative fecal scores. The high protective efficacy of the probiotic cocktail regimens was attributed to stimulation of IFN-γ+ T cell responses, increased production of intestinal IgA and IgG, and maintenance of healthy intestinal morphology (manifested as longer villi compared with the control group). Therefore, probiotic cocktail regimens containing LGG+EcN and RB may represent highly efficacious strategies to prevent and treat HuNoV gastroenteritis, and potentially other human enteric pathogens.

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Norovirus Vaccines and Potential Antinorovirus Drugs: Recent Advances and Future Perspectives

Cited by 33 publications

References 129 publications

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

High Protective Efficacy of Probiotics and Rice Bran against Human Norovirus Infection and Diarrhea in Gnotobiotic Pigs

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