A Peptide Inhibitor Derived from the Conserved Ectodomain Region of <scp>DENV</scp> Membrane (M) Protein with Activity Against Dengue Virus Infection

Panya, Aussara; Sawasdee, Nunghathai; Junking, Mutita; Srisawat, Chatchawan; Choowongkomon, Kiattawee; Yenchitsomanus, Pa‐thai

doi:10.1111/cbdd.12576

Cited by 36 publications

(23 citation statements)

References 34 publications

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“…Our research group previously reported on peptide inhibitors that bind to the E protein of DENV2. The small peptides EF and MLH40 that we studied and reported could bind to the E protein of DENV2 in the initial step, and this was supported by time‐of‐addition assay. Consistent with our previous small peptide EF and MLH40 findings, pretreatment of DENV2 with the novel peptides in this study caused dramatic reduction in DENV2 infection.…”

Section: Discussionsupporting

confidence: 52%

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Novel bioactive peptides demonstrating anti‐dengue virus activity isolated from the Asian medicinal plant Acacia Catechu

et al. 2018

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The therapeutic activities of food-derived bioactive proteins and peptides are attracting increased attention within the research community. Medicinal plants used in traditional medicines are an excellent source of bioactive proteins and peptides, especially those traditionally prepared by water extraction for use as tea or food supplement. In this study, novel bioactive peptides were isolated from enzymatic digests of 33 Thai medicinal plants. The inhibitory activity of each against dengue virus (DENV) infection was investigated. Of 33 plants, peptides from Acacia catechu extract demonstrated the most pronounced anti-DENV activity. Half maximal inhibitory concentration of 0.18 μg/ml effectively inhibited DENV foci formation. Treatment with 1.25 μg/ml crude peptide extract could reduce virus production less than 100-fold with no observable cell toxicity. Peptide sequences were determined by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Two bioactive peptides isolated from Acacia catechu inhibited DENV foci formation >90% at the concentration of 50 μM; therefore, they are recommended for further investigation as antiviral peptides against DENV infection.

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Section: Discussionsupporting

confidence: 52%

“…Our research group is committed to the continued search for anti‐DENV agents . We recently reported on our in silico investigation of anti‐DENV peptides . In this in vitro study, we set forth to identify bioactive peptides with anti‐DENV activity in Thai medicinal plants.…”

Section: Introductionmentioning

confidence: 99%

Novel bioactive peptides demonstrating anti‐dengue virus activity isolated from the Asian medicinal plant Acacia Catechu

et al. 2018

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“…M protein contains 75 amino acids; the N-terminal 40 amino acids form an ectodomain containing a hydrophobic loop followed by an amphipathic helical portion, and the C-terminal 35 amino acids form a transmembrane region (14). The amphipathic helical portion interacts with envelope protein (E) to promote DENV invasion, packing mature, and release (15)(16)(17)(18). These studies suggest that M plays an important role in DENV infection.…”

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confidence: 99%

Dengue Virus M Protein Promotes NLRP3 Inflammasome Activation To Induce Vascular Leakage in Mice

Pan

Zhang

Liu

et al. 2019

J Virol

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Dengue virus (DENV) infection causes serious clinical symptoms, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular permeability change is the main feature of the diseases, and the abnormal expression of proinflammatory cytokines is the important cause of vascular permeability change. However, the mechanism underlying vascular permeability induced by DENV has not been fully elucidated. Here, we reveal a distinct mechanism by which DENV infection promotes NLRP3 inflammasome activation and interleukin-1 beta (IL-1β) release to induce endothelial permeability and vascular leakage in mice. DENV M protein interacts with NLRP3 to facilitate NLRP3 inflammasome assembly and activation, which induce proinflammatory cytokine IL-1β activation and release. Notably, M can induce vascular leakage in mouse tissues by activating the NLRP3 inflammasome and IL-1β. More importantly, inflammatory cell infiltration and tissue injuries are induced by M in wild-type (WT) mouse tissues, but they are not affected by M in NLRP3 knockout (NLRP3−/−) mouse tissues. Evans blue intensities in WT mouse tissues are significantly higher than in NLRP3−/− mouse tissues, demonstrating an essential role of NLRP3 in M-induced vascular leakages in mice. Therefore, we propose that upon DENV infection, M interacts with NLRP3 to facilitate inflammasome activation and IL-1β secretion, which lead to the induction of endothelial permeability and vascular leakage in mouse tissues. The important role of the DENV-M-NLRP3-IL-1β axis in the induction of vascular leakage provides new insights into the mechanisms underlying DENV pathogenesis and DENV-associated DHF and DSS development. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen, and infections by this virus are prevalent in over 100 tropical and subtropical countries or regions, with approximately 2.5 billion people at risk. DENV infection induces a spectrum of clinical symptoms, ranging from classical dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Therefore, it is important to understand the mechanisms underlying DENV pathogenesis. In this study, we reveal that the DENV membrane protein (M) interacts with the host NLRP3 protein to promote NLRP3 inflammasome activation, which leads to the activation and release of a proinflammatory cytokine, interleukin-1 beta (IL-1β). More importantly, we demonstrate that M protein can induce vascular permeability and vascular leakage and that NLRP3 is required for M-induced vascular leakage in mouse tissues. Collectively, this study reveals a distinct mechanism underlying DENV pathogeneses and provides new insights into the development of therapeutic agents for DENV-associated diseases.

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“…Regarding peptidic inhibitors of dengue virus, three main strategies have been followed: (1) in silico designed peptides, (2) peptides mimicking the viral protein sequences, and (3) peptides obtained by panning against viral proteins. While the development of antiviral peptides against DENV has been dominated by reports using the first two approaches [ 61 – 64 ], a few attempts have been made to make use of the versatile phage display technology to find new antivirals. The peptides identified using random peptide libraries include those reported by Panya et al, 2014 [ 65 ], which target the envelope hydrophobic pocket, and those reported by Chew et al, 2015 [ 66 ], which target the full DENV2 virion.…”

Section: Resultsmentioning

confidence: 99%

Phage-Displayed Peptides Selected to Bind Envelope Glycoprotein Show Antiviral Activity against Dengue Virus Serotype 2

Guardia

Quijada

Lleonart

2017

Advances in Virology

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Dengue virus is a growing public health threat that affects hundreds of million peoples every year and leave huge economic and social damage. The virus is transmitted by mosquitoes and the incidence of the disease is increasing, among other causes, due to the geographical expansion of the vector's range and the lack of effectiveness in public health interventions in most prevalent countries. So far, no highly effective vaccine or antiviral has been developed for this virus. Here we employed phage display technology to identify peptides able to block the DENV2. A random peptide library presented in M13 phages was screened with recombinant dengue envelope and its fragment domain III. After four rounds of panning, several binding peptides were identified, synthesized, and tested against the virus. Three peptides were able to block the infectivity of the virus while not being toxic to the target cells. Blind docking simulations were done to investigate the possible mode of binding, showing that all peptides appear to bind domain III of the protein and may be mostly stabilized by hydrophobic interactions. These results are relevant to the development of novel therapeutics against this important virus.

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A Peptide Inhibitor Derived from the Conserved Ectodomain Region of DENV Membrane (M) Protein with Activity Against Dengue Virus Infection

Cited by 36 publications

References 34 publications

Novel bioactive peptides demonstrating anti‐dengue virus activity isolated from the Asian medicinal plant Acacia Catechu

Novel bioactive peptides demonstrating anti‐dengue virus activity isolated from the Asian medicinal plant Acacia Catechu

Dengue Virus M Protein Promotes NLRP3 Inflammasome Activation To Induce Vascular Leakage in Mice

Phage-Displayed Peptides Selected to Bind Envelope Glycoprotein Show Antiviral Activity against Dengue Virus Serotype 2

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