The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Mark Von Itzstein - One of the best experts on this subject based on the ideXlab platform.
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exploring inhibitor structural features required to engage the 216 loop of human Parainfluenza Virus type 3 hemagglutinin neuraminidase
MedChemComm, 2017Co-Authors: Ibrahim M Eldeeb, Larissa Dirr, Patrice Guillon, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type-3 is a leading cause of acute respiratory infection in infants and children. There is currently neither vaccine nor clinically effective treatment for Parainfluenza Virus infection. Hemagglutinin-neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for inhibitor development. In this study, we explore the structural features required for Neu2en derivatives to efficiently lock-open the 216-loop of the human Parainfluenza Virus type-3 hemagglutinin-neuraminidase protein.
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The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed†
Angewandte Chemie, 2015Co-Authors: Larissa Dirr, Patrice Guillon, Ibrahim M. El-deeb, Cindy J. Carroux, Leonard M. G. Chavas, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human Parainfluenza Virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this Virus. Herein, we used 1H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in Virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.
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Exploring human Parainfluenza Virus type-1 hemagglutinin-neuraminidase as a target for inhibitor discovery.
Journal of Medicinal Chemistry, 2014Co-Authors: Ibrahim M. El-deeb, Patrice Guillon, Moritz Winger, Tanguy Eveno, Thomas Haselhorst, Jeffrey Clifford Dyason, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type 1 is the major cause of croup in infants and young children. There is currently neither vaccine nor clinically effective treatment for Parainfluenza Virus infection. Hemagglutinin–neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en)-based inhibitor development. In this study, we explore the effect of C-5 modifications on the potency of Neu5Ac2en derivatives that target the human Parainfluenza type-1 hemagglutinin–neuraminidase protein. Our study demonstrates that the replacement of the Neu5Ac2en C-5 acetamido moiety with more hydrophobic alkane-based moieties improves the inhibitory potency for both hemagglutinin–neuraminidase functions. These findings shed light on the importance of C-5 substitution on Neu5Ac2en in the design of novel sialic acid-based inhibitors that target human Parainfluenza type-1 hemagglutinin–neuraminidase.
Larissa Dirr - One of the best experts on this subject based on the ideXlab platform.
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Structural and Functional Insights into Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase
2020Co-Authors: Larissa DirrAbstract:Viruses constitute one of the greatest health threats to mankind and viral diseases have a major economic impact across the world. The family Paramyxoviridae includes Viruses of significant medical and veterinary importance, including human respiratory pathogens like the human Parainfluenza Viruses (hPIVs). Among them, human Parainfluenza Virus type 3 (hPIV-3) is the second leading cause of respiratory disease in infants and young children after human respiratory syncytial Virus. Apart from being a significant childhood pathogen, hPIV-3 is a particular concern for chronically ill, elderly and immunocompromised patients with mortality rates of up to 50%. Despite ongoing efforts, there are currently neither vaccines nor specific antiviral therapies available for the treatment or prevention of Parainfluenza Virus infections. Two glycoproteins, namely the haemagglutinin-neuraminidase (HN) and the fusion (F) protein, decorate the viral surface. The HN glycoprotein encompasses three key roles in the Virus' life cycle: attachment to host cell receptors (cell adhesion through recognition by the sialic acid, N-acetylneuraminic acid, Neu5Ac), involvement in the fusion process, and host cell receptor destruction (facilitating viral progeny release). This multifunctional role makes HN an ideal antiviral target and within this thesis, the discovery of novel anti-Parainfluenza Virus inhibitors is presented.
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exploring inhibitor structural features required to engage the 216 loop of human Parainfluenza Virus type 3 hemagglutinin neuraminidase
MedChemComm, 2017Co-Authors: Ibrahim M Eldeeb, Larissa Dirr, Patrice Guillon, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type-3 is a leading cause of acute respiratory infection in infants and children. There is currently neither vaccine nor clinically effective treatment for Parainfluenza Virus infection. Hemagglutinin-neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for inhibitor development. In this study, we explore the structural features required for Neu2en derivatives to efficiently lock-open the 216-loop of the human Parainfluenza Virus type-3 hemagglutinin-neuraminidase protein.
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The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed†
Angewandte Chemie, 2015Co-Authors: Larissa Dirr, Patrice Guillon, Ibrahim M. El-deeb, Cindy J. Carroux, Leonard M. G. Chavas, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human Parainfluenza Virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this Virus. Herein, we used 1H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in Virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.
Caroline B Hall - One of the best experts on this subject based on the ideXlab platform.
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Parainfluenza Virus infection of young children estimates of the population based burden of hospitalization
The Journal of Pediatrics, 2009Co-Authors: Geoffrey A Weinberg, Caroline B Hall, Marika K Iwane, Katherine A Poehling, Kathryn M Edwards, Marie R Griffin, Mary Allen Staat, Aaron T Curns, Dean D Erdman, Peter G SzilagyiAbstract:Objective To determine the population-based inpatient disease burden of Parainfluenza Virus in children Study design The New Vaccine Surveillance Network (NVSN) enrolled children 95% of all hospitalized children from each county. Combined nasal turbinate/throat swabs were tested for Parainfluenza Virus (PIV), respiratory syncytial Virus, and influenza Virus with culture and reverse-transcription-polymerase chain reaction. Both parental interviews and medical chart reviews were conducted. Age-specific population-based hospitalization rates were calculated. Results From October 2000 through September 2004, 2798 children were enrolled. A total of 191 PIVs were identified from 189 children (6.8% of enrolled: 73 PIV type 1, 23 PIV type 2, and 95 PIV type 3), compared with 521 respiratory syncytial Viruses and 159 influenza Viruses. Mean PIV hospitalization rates were 3.01, 1.73, 1.53, 0.39, and 1.02 per 1000 children per year for ages 0 to 5 months, 6 to 11 months, 12 to 23 months, 24 to 59 months, and 0 to 59 months, respectively. Conclusions PIV accounted for 6.8% of all hospitalizations for fever, acute respiratory illnesses, or both in children
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respiratory syncytial Virus and Parainfluenza Virus
The New England Journal of Medicine, 2001Co-Authors: Caroline B HallAbstract:Respiratory syncytial Virus (RSV), originally recovered from a colony of chimpanzees with coryza and designated chimpanzee coryza agent,1,2 and human Parainfluenza Virus types 1, 2, 3, and 4 have been known primarily as respiratory pathogens in young children. They are now recognized as important pathogens in adults as well. Adults infected with these Viruses tend to have more variable and less distinctive clinical findings than children, and the viral cause of the infection is often unsuspected. The consistency of the annual outbreaks of these agents and the frequency of reinfection suggest that they impose a considerable, but ill-defined, disease . . .
Robert A Lamb - One of the best experts on this subject based on the ideXlab platform.
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on the stability of Parainfluenza Virus 5 f proteins
Journal of Virology, 2015Co-Authors: Taylor A Poor, Albert S Song, Brett D Welch, Christopher A Kors, Theodore S Jardetzky, Robert A LambAbstract:The crystal structure of the F protein (prefusion form) of the paramyxoVirus Parainfluenza Virus 5 (PIV5) WR isolate was determined. We investigated the basis by which point mutations affect fusion in PIV5 isolates W3A and WR, which differ by two residues in the F ectodomain. The P22 stabilizing site acts through a local conformational change and a hydrophobic pocket interaction, whereas the S443 destabilizing site appears sensitive to both conformational effects and amino acid charge/polarity changes.
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fusion activation by a headless Parainfluenza Virus 5 hemagglutinin neuraminidase stalk suggests a modular mechanism for triggering
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Sayantan Bose, Brett D Welch, Theodore S Jardetzky, Aarohi Zokarkar, George P Leser, Robert A LambAbstract:The Paramyxoviridae family of enveloped Viruses enters cells through the concerted action of two viral glycoproteins. The receptor-binding protein, hemagglutinin-neuraminidase (HN), H, or G, binds its cellular receptor and activates the fusion protein, F, which, through an extensive refolding event, brings viral and cellular membranes together, mediating Virus–cell fusion. However, the underlying mechanism of F activation on receptor engagement remains unclear. Current hypotheses propose conformational changes in HN, H, or G propagating from the receptor-binding site in the HN, H, or G globular head to the F-interacting stalk region. We provide evidence that the receptor-binding globular head domain of the paramyxoVirus Parainfluenza Virus 5 HN protein is entirely dispensable for F activation. Considering together the crystal structures of HN from different paramyxoViruses, varying energy requirements for fusion activation, F activation involving the Parainfluenza Virus 5 HN stalk domain, and properties of a chimeric paramyxoVirus HN protein, we propose a simple model for the activation of paramyxoVirus fusion.
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comparison of differing cytopathic effects in human airway epithelium of Parainfluenza Virus 5 w3a Parainfluenza Virus type 3 and respiratory syncytial Virus
Virology, 2011Co-Authors: Liqun Zhang, Peter L Collins, Robert A Lamb, Raymond J PicklesAbstract:Parainfluenza Virus 5 (PIV5) infects a wide range of animals including dogs, pigs, cats, and humans; however, its association with disease in humans remains controversial. In contrast to Parainfluenza Virus 3 (PIV3) or respiratory syncytial Virus (RSV), PIV5 is remarkably non-cytopathic in monolayer cultures of immortalized epithelial cells. To compare the cytopathology produced by these Viruses in a relevant human tissue, we infected an in vitro model of human ciliated airway epithelium and measured outcomes of cytopathology. PIV5, PIV3 and, RSV all infected ciliated cells, and PIV5 and PIV3 infection was dependent on sialic acid residues. Only PIV5-infected cells formed syncytia. PIV5 infection resulted in a more rapid loss of infected cells by shedding of infected cells into the lumen. These studies revealed striking differences in cytopathology of PIV5 versus PIV3 or RSV and indicate the extent of cytopathology determined in cell-lines does not predict events in differentiated airway cells.
Patrice Guillon - One of the best experts on this subject based on the ideXlab platform.
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exploring inhibitor structural features required to engage the 216 loop of human Parainfluenza Virus type 3 hemagglutinin neuraminidase
MedChemComm, 2017Co-Authors: Ibrahim M Eldeeb, Larissa Dirr, Patrice Guillon, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type-3 is a leading cause of acute respiratory infection in infants and children. There is currently neither vaccine nor clinically effective treatment for Parainfluenza Virus infection. Hemagglutinin-neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for inhibitor development. In this study, we explore the structural features required for Neu2en derivatives to efficiently lock-open the 216-loop of the human Parainfluenza Virus type-3 hemagglutinin-neuraminidase protein.
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The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin-Neuraminidase Revealed†
Angewandte Chemie, 2015Co-Authors: Larissa Dirr, Patrice Guillon, Ibrahim M. El-deeb, Cindy J. Carroux, Leonard M. G. Chavas, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type 3 (hPIV-3) is one of the leading causes for lower respiratory tract disease in children, with neither an approved antiviral drug nor vaccine available to date. Understanding the catalytic mechanism of human Parainfluenza Virus haemagglutinin-neuraminidase (HN) protein is key to the design of specific inhibitors against this Virus. Herein, we used 1H NMR spectroscopy, X-ray crystallography, and virological assays to study the catalytic mechanism of the HN enzyme activity and have identified the conserved Tyr530 as a key amino acid involved in catalysis. A novel 2,3-difluorosialic acid derivative showed prolonged enzyme inhibition and was found to react and form a covalent bond with Tyr530. Furthermore, the novel derivative exhibited enhanced potency in Virus blockade assays relative to its Neu2en analogue. These outcomes open the door for a new generation of potent inhibitors against hPIV-3 HN.
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Exploring human Parainfluenza Virus type-1 hemagglutinin-neuraminidase as a target for inhibitor discovery.
Journal of Medicinal Chemistry, 2014Co-Authors: Ibrahim M. El-deeb, Patrice Guillon, Moritz Winger, Tanguy Eveno, Thomas Haselhorst, Jeffrey Clifford Dyason, Mark Von ItzsteinAbstract:Human Parainfluenza Virus type 1 is the major cause of croup in infants and young children. There is currently neither vaccine nor clinically effective treatment for Parainfluenza Virus infection. Hemagglutinin–neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en)-based inhibitor development. In this study, we explore the effect of C-5 modifications on the potency of Neu5Ac2en derivatives that target the human Parainfluenza type-1 hemagglutinin–neuraminidase protein. Our study demonstrates that the replacement of the Neu5Ac2en C-5 acetamido moiety with more hydrophobic alkane-based moieties improves the inhibitory potency for both hemagglutinin–neuraminidase functions. These findings shed light on the importance of C-5 substitution on Neu5Ac2en in the design of novel sialic acid-based inhibitors that target human Parainfluenza type-1 hemagglutinin–neuraminidase.
