scholarly journals Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates

2021 ◽  
Vol 22 (16) ◽  
pp. 8418
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Daniel L. Hurdiss ◽  
Nitesh Mistry ◽  
C. David Andersson ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Host Cells ◽  
Scaffold Hopping ◽  
Corneal Epithelial ◽  
Acetylneuraminic Acid ◽  
Design And Synthesis ◽  
Coxsackievirus A24 Variant ◽  
Human Corneal Epithelial Cells ◽  
Eye Infection ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

scholarly journals Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37 – Viruses That Cause Highly Contagious Eye Infections

2020 ◽  
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Nitesh Mistry ◽  
Georg Zocher ◽  
Weixing Qian ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Agents ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Coxsackievirus A24 Variant ◽  
Causative Agents ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection, and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

scholarly journals Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37 – Viruses That Cause Highly Contagious Eye Infections

2020 ◽  
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Nitesh Mistry ◽  
Georg Zocher ◽  
Weixing Qian ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Agents ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Coxsackievirus A24 Variant ◽  
Causative Agents ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection, and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

scholarly journals Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

2021 ◽  
Vol 9 ◽  
Author(s):  
Rosa Ester Forgione ◽  
Cristina Di Carluccio ◽  
Francesco Milanesi ◽  
Marie Kubota ◽  
Ferran Fabregat Nieto ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Mumps Virus ◽  
Host Cells ◽  
Neuraminidase Inhibitors ◽  
Acetylneuraminic Acid ◽  
Design And Synthesis ◽  
Molecular Features ◽  
Viral Hemagglutinin ◽  
Viral Glycoproteins

The inhibition of surface viral glycoproteins offers great potential to hamper the attachment of viruses to the host cells surface and the spreading of viral infection. Mumps virus (MuV) is the etiological agent of the mumps infectious disease and causes a wide spectrum of mild to severe symptoms due to the inflammation of the salivary glands. Here we focus our attention on the hemagglutinin-neuraminidase (HN) isolated from MuV SBL-1 strain. We describe the molecular features of host sialoglycans recognition by HN protein by means of NMR, fluorescence assays and computational studies. Furthermore, we also describe the synthesis of a N-acetylneuraminic acid-derived thiotrisaccharide targeting the viral protein, and the corresponding 3D-complex. Our results provide the basis to improve the design and synthesis of potent viral hemagglutinin-neuraminidase inhibitors.

scholarly journals Influence of Pseudomonas autoinducer N-3-oxododecanoyl homoserine lactone on human corneal epithelial cells

2020 ◽  
pp. 153537022096983
Author(s):  
Renjian Hu ◽  
Kelan Yuan ◽  
Jie Zhou ◽  
Yue Zhang ◽  
Jiao Zheng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Homoserine Lactone ◽  
Host Cells ◽  
Time Dependent ◽  
Cell Counting ◽  
Dependent Manner ◽  
Corneal Epithelial Cells ◽  
Corneal Epithelial ◽  
Human Corneal Epithelial Cells

The quorum-sensing (QS) signaling-dependent extracellular virulence factors of Pseudomonas aeruginosa can cause infections such as P. aeruginosa keratitis. P. aeruginosa communicates by secreting and sensing small chemical molecules called autoinducers in QS system. The key QS signal molecule, N-3-oxododecanoyl-homoserine lactone (3OC12HSL), can affect the behavior of host cells and initiate immune response. In this report we investigated the influence of 3OC12HSL on human corneal epithelial cells (HCECs) and the mechanisms of 3OC12HSL on activated toll-like receptor 2 (TLR2)-dependent interleukin-8 (IL-8) secretion in HCECs. Cells were cultured under different concentrations of 3OC12HSL. Cell viability was assessed using Crystal violet staining and the cell counting kit-8 assay. We demonstrated the administration of 3OC12HSL decreased HCEC viability and survival in a concentration- and time-dependent manner. At high concentrations, 3OC12HSL rapidly promoted a time-dependent increase in the expressions of TLR2 and TLR4. It was found that the nuclear translocation and expression of nuclear factor-κB (NF-κB) were also increased in response to 3OC12HSL treatment. The significantly elevated expressions of TLR2, TLR4, and NF-κB, encouraged us to further test their mechanisms that cause inflammatory response. Among the inflammatory factors examined (IL-6, IL-8, IL-10, and TNF-α), we found that IL-8 was significantly increased after treatment with 3OC12HSL and its expression was inhibited when TLR2 was specifically blocked or silenced. These results indicated that the QS signaling molecule 3OC12HSL could be recognized by the host innate immune system in HCECs. This recognition then triggered an immune inflammatory response involving the activation of TLR2 and an increase in expression of IL-8. This crosstalk between 3OC12HSL and host immunity in HCECs contributes to the development and progression of P. aeruginosa keratitis.

scholarly journals Sialic Acid Is a Cellular Receptor for Coxsackievirus A24 Variant, an Emerging Virus with Pandemic Potential

2008 ◽  
Vol 82 (6) ◽  
pp. 3061-3068 ◽  
Author(s):  
Emma C. Nilsson ◽  
Fariba Jamshidi ◽  
Susanne M. C. Johansson ◽  
M. Steven Oberste ◽  
Niklas Arnberg
Keyword(s):  
Sialic Acid ◽  
Influenza A ◽  
Cellular Receptor ◽  
Virus Binding ◽  
Corneal Epithelial ◽  
Coxsackievirus A24 Variant ◽  
Emerging Virus ◽  
Enterovirus Type ◽  
Protease Treatment ◽  
Coxsackievirus A24

ABSTRACT Binding to target cell receptors is a critical step in the virus life cycle. Coxsackievirus A24 variant (CVA24v) has pandemic potential and is a major cause of acute hemorrhagic conjunctivitis, but its cellular receptor has hitherto been unknown. Here we show that CVA24v fails to bind to and infect CHO cells defective in sialic acid expression. Binding of CVA24v to and infection of corneal epithelial cells are efficiently inhibited by treating cells with a sialic acid-cleaving enzyme or sialic acid-binding lectins and by treatment of the virus with soluble, multivalent sialic acid. Protease treatment of cells efficiently inhibited virus binding, suggesting that the receptor is a sialylated glycoprotein. Like enterovirus type 70 and influenza A virus, CVA24v can cause pandemics. Remarkably, all three viruses use the same receptor. Since several unrelated viruses with tropism for the eye use this receptor, sialic acid-based antiviral drugs that prevent virus entry may be useful for topical treatment of such infections.

scholarly journals Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction

RSC Advances ◽  
2022 ◽  
Vol 12 (4) ◽  
pp. 2319-2331
Author(s):  
Emil Johansson ◽  
Rémi Caraballo ◽  
Georg Zocher ◽  
Nitesh Mistry ◽  
Niklas Arnberg ◽  
...  
Keyword(s):  
Neuraminic Acid ◽  
Acute Hemorrhagic Conjunctivitis ◽  
Coxsackievirus A24 Variant ◽  
Eye Infection ◽  
Coxsackievirus A24

Coxsackievirus A24 variant (CVA24v) is responsible for several outbreaks and two pandemics of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC).

scholarly journals Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 437
Author(s):  
Dean Gilham ◽  
Audrey L. Smith ◽  
Li Fu ◽  
Dalia Y. Moore ◽  
Abenaya Muralidharan ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Host Cells ◽  
Protein Inhibitor ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Surface Receptors ◽  
Bet Inhibitor ◽  
Epigenetic Machinery ◽  
Unexplored Area

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

scholarly journals A combination of CMC and α-MSH inhibited ROS activated NLRP3 inflammasome in hyperosmolarity stressed HCECs and scopolamine-induced dry eye rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Lv ◽  
Chenchen Chu ◽  
Ke Liu ◽  
Yusha Ru ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Dry Eye ◽  
Nlrp3 Inflammasome ◽  
Ocular Surface ◽  
Combined Treatment ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
Corneal Epithelial ◽  
Melanocyte Stimulating Hormone ◽  
Human Corneal Epithelial Cells ◽  
Conjunctival Goblet Cells

AbstractAn important mechanism involved in dry eye (DE) is the association between tear hyperosmolarity and inflammation severity. Inflammation in DE might be mediated by the NLRP3 inflammasome, which activated by exposure to reactive oxygen species (ROS). A combination of carboxymethylcellulose (CMC) and α-melanocyte stimulating hormone (α-MSH) may influence DE through this mechanism, thus avoiding defects of signal drug. In this study, we assessed whether treatment comprising CMC combined with α-MSH could ameliorate ocular surface function; we found that it promoted tear secretion, reduced the density of fluorescein sodium staining, enhanced the number of conjunctival goblet cells, and reduced the number of corneal apoptotic cells. Investigation of the underlying mechanism suggested that the synergistic effect of combined treatment alleviated DE inflammation through reduction of ROS level and inhibition of the NLRP3 inflammasome in human corneal epithelial cells. These findings indicate that combined CMC + α-MSH treatment could ameliorate lesions and restore ocular surface function in patients with DE through reduction of ROS level and inhibition of NLRP3 signalling.

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