Antiviral efficacy of orally delivered neoagarohexaose, a nonconventional TLR4 agonist, against norovirus infection in mice

Kim, Minwoo; Lee, Ji Eun; Cho, Hee; Jung, Hae Gwang; Lee, Wooseong; Seo, Han Young; Lee, Soung Hoon; Ahn, Dong‐Gyu; Kim, Seong Jun; Yu, Je-Wook; Oh, Jisun

doi:10.1016/j.biomaterials.2020.120391

Cited by 14 publications

(9 citation statements)

References 83 publications

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“…The oligosaccharide NA6 is derived from agarose, a major component of red algae (Rhodophyta) cell walls. Kim et al examined the effect of NA6 administration on immune activation in vitro using a RAW264.7 cell line ( Table 4 ) [ 146 ]. This study determined that NA6 is an agonist for the TLR4 signaling pathway, important in the production of proinflammatory cytokines (TNF, interleukins) and interferons (IFNs).…”

Section: Viral Pathogenesismentioning

confidence: 99%

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Viral inhibitors derived from macroalgae, microalgae, and cyanobacteria: A review of antiviral potential throughout pathogenesis

et al. 2021

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Viruses are abiotic obligate parasites utilizing complex mechanisms to hijack cellular machinery and reproduce, causing multiple harmful effects in the process. Viruses represent a growing global health concern; at the time of writing, COVID-19 has killed at least two million people around the world and devastated global economies. Lingering concern regarding the virus' prevalence yet hampers return to normalcy. While catastrophic in and of itself, COVID-19 further heralds in a new era of human-disease interaction characterized by the emergence of novel viruses from natural sources with heretofore unseen frequency. Due to deforestation, population growth, and climate change, we are encountering more viruses that can infect larger groups of people with greater ease and increasingly severe outcomes. The devastation of COVID-19 and forecasts of future human/disease interactions call for a creative reconsideration of global response to infectious disease. There is an urgent need for accessible, cost-effective antiviral (AV) drugs that can be mass-produced and widely distributed to large populations. Development of AV drugs should be informed by a thorough understanding of viral structure and function as well as human biology. To maximize efficacy, minimize cost, and reduce development of drug-resistance, these drugs would ideally operate through a varied set of mechanisms at multiple stages throughout the course of infection. Due to their abundance and diversity, natural compounds are ideal for such comprehensive therapeutic interventions. Promising sources of such drugs are found throughout nature; especially remarkable are the algae, a polyphyletic grouping of phototrophs that produce diverse bioactive compounds. While not much literature has been published on the subject, studies have shown that these compounds exert antiviral effects at different stages of viral pathogenesis. In this review, we follow the course of viral infection in the human body and evaluate the AV effects of algae-derived compounds at each stage. Specifically, we examine the AV activities of algae-derived compounds at the entry of viruses into the body, transport through the body via the lymph and blood, infection of target cells, and immune response. We discuss what is known about algae-derived compounds that may interfere with the infection pathways of SARS-CoV-2; and review which algae are promising sources for AV agents or AV precursors that, with further investigation, may yield life-saving drugs due to their diversity of mechanisms and exceptional pharmaceutical potential.

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Section: Viral Pathogenesismentioning

confidence: 99%

“…NA6 boosted induction of IFN-β and upregulated IFN-regulatory factor-1, an IFN-stimulated gene. Oral administration of NA6 activated TLR4 signaling and thereby reduced norovirus loads [ 146 ].…”

Section: Viral Pathogenesismentioning

confidence: 99%

Viral inhibitors derived from macroalgae, microalgae, and cyanobacteria: A review of antiviral potential throughout pathogenesis

et al. 2021

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“…NAOSs, which can be produced by hydrolyzing agarose extracted from red macroalgae by endo-type β-agarase, have been reported to possess various health benefits [ 22 – 27 ]. NeoDP4, which is a representative NAOS, has been reported to have various biological properties [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…As a non-digestible diet, agarose, a polysaccharide obtained from red macroalgae, is commonly used as dietary fiber by East Asians [ 21 ]. Neoagarooligosaccharides (NAOSs) derived from agarose were found to have various physiological and biological activities, including anti-obesity, anti-diabetic, anti-inflammatory, anti-viral, and anti-tumor activities [ 22 – 27 ]. Moreover, in vivo experiments confirmed that NAOSs have a prebiotic effect [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Production of neoagarooligosaccharides by probiotic yeast Saccharomyces cerevisiae var. boulardii engineered as a microbial cell factory

Jin

Liu

et al. 2021

Microb Cell Fact

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Background Saccharomyces cerevisiae var. boulardii is a representative probiotic yeast that has been widely used in the food and pharmaceutical industries. However, S. boulardii has not been studied as a microbial cell factory for producing useful substances. Agarose, a major component of red macroalgae, can be depolymerized into neoagarooligosaccharides (NAOSs) by an endo-type β-agarase. NAOSs, including neoagarotetraose (NeoDP4), are known to be health-benefiting substances owing to their prebiotic effect. Thus, NAOS production in the gut is required. In this study, the probiotic yeast S. boulardii was engineered to produce NAOSs by expressing an endo-type β-agarase, BpGH16A, derived from a human gut bacterium Bacteroides plebeius. Results In total, four different signal peptides were compared in S. boulardii for protein (BpGH16A) secretion for the first time. The SED1 signal peptide derived from Saccharomyces cerevisiae was selected as optimal for extracellular production of NeoDP4 from agarose. Expression of BpGH16A was performed in two ways using the plasmid vector system and the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system. The production of NeoDP4 by engineered S. boulardii was verified and quantified. NeoDP4 was produced by S. boulardii engineered using the plasmid vector system and CRISPR-Cas9 at 1.86 and 0.80 g/L in a 72-h fermentation, respectively. Conclusions This is the first report on NAOS production using the probiotic yeast S. boulardii. Our results suggest that S. boulardii can be considered a microbial cell factory to produce health-beneficial substances in the human gut. Graphical abstract

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“…Additionally, a recent report demonstrated that NA4 can selectively modulate gut microbial community composition and regulate multiple intestine metabolites to alleviate inflammation [ 26 ]. NA6 was reported to possess a potential antitumor immunity and act as a cell modulator towards melanoma, and afterwards was verified to have an antivirus inborn immunity against norovirus [ 12 , 27 ]. Owing to these properties, in this study, rAgaW1540 can be further applied in food, medicine, and cosmetic industries.…”

Section: Discussionmentioning

confidence: 99%

Expression and Characterization of a Novel Cold-Adapted and Stable β-Agarase Gene agaW1540 from the Deep-Sea Bacterium Shewanella sp. WPAGA9

Wang

Yan

et al. 2021

Marine Drugs

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The neoagaro-oligosaccharides, degraded from agarose by agarases, are important natural substances with many bioactivities. In this study, a novel agarase gene, agaW1540, from the genome of a deep-sea bacterium Shewanella sp. WPAGA9, was expressed, and the recombinant AgaW1540 (rAgaW1540) displayed the maximum activity under the optimal pH and temperature of 7.0 and 35 °C, respectively. rAgaW1540 retained 85.4% of its maximum activity at 0 °C and retained more than 92% of its maximum activity at the temperature range of 20–40 °C and the pH range of 4.0–9.0, respectively, indicating its extensive working temperature and pH values. The activity of rAgaW1540 was dramatically suppressed by Cu2+ and Zn2+, whereas Fe2+ displayed an intensification of enzymatic activity. The Km and Vmax of rAgaW1540 for agarose degradation were 15.7 mg/mL and 23.4 U/mg, respectively. rAgaW1540 retained 94.7%, 97.9%, and 42.4% of its maximum activity after incubation at 20 °C, 25 °C, and 30 °C for 60 min, respectively. Thin-layer chromatography and ion chromatography analyses verified that rAgaW1540 is an endo-acting β-agarase that degrades agarose into neoagarotetraose and neoagarohexaose as the main products. The wide variety of working conditions and stable activity at room temperatures make rAgaW1540an appropriate bio-tool for further industrial production of neoagaro-oligosaccharides.

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Antiviral efficacy of orally delivered neoagarohexaose, a nonconventional TLR4 agonist, against norovirus infection in mice

Cited by 14 publications

References 83 publications

Viral inhibitors derived from macroalgae, microalgae, and cyanobacteria: A review of antiviral potential throughout pathogenesis

Viral inhibitors derived from macroalgae, microalgae, and cyanobacteria: A review of antiviral potential throughout pathogenesis

Production of neoagarooligosaccharides by probiotic yeast Saccharomyces cerevisiae var. boulardii engineered as a microbial cell factory

Expression and Characterization of a Novel Cold-Adapted and Stable β-Agarase Gene agaW1540 from the Deep-Sea Bacterium Shewanella sp. WPAGA9

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