The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Christopher W Cairo - One of the best experts on this subject based on the ideXlab platform.
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molecular dynamics simulations of viral Neuraminidase inhibitors with the human Neuraminidase enzymes insights into isoenzyme selectivity
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Michele R Richards, Tianlin Guo, Carmanah D Hunter, Christopher W CairoAbstract:Abstract Inhibitors of viral Neuraminidase enzymes have been previously developed as therapeutics. Humans can express multiple forms of Neuraminidase enzymes (NEU1, NEU2, NEU3, NEU4) that share a similar active site and enzymatic mechanism with their viral counterparts. Using a panel of purified human Neuraminidase enzymes, we tested the inhibitory activity of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir, oseltamivir, and peramivir against each of the human isoenzymes. We find that, with the exceptions of DANA and zanamivir, these compounds show generally poor activity against the human Neuraminidase enzymes. To provide insight into the interactions of viral inhibitors with human Neuraminidases, we conducted molecular dynamics simulations using homology models based on coordinates reported for NEU2. Simulations revealed that an organized water is displaced by zanamivir in binding to NEU2 and NEU3 and confirmed the critical importance of engaging the binding pocket of the C7–C9 glycerol sidechain. Our results suggest that compounds designed to target the human Neuraminidases should provide more selective tools for interrogating these enzymes. Furthermore, they emphasize a need for additional structural data to enable structure-based drug design in these systems.
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Persistent reduction in sialylation of cerebral glycoproteins following postnatal inflammatory exposure
BMC, 2018Co-Authors: Ekaterina P. Demina, Christopher W Cairo, Alexey V. Pshezhetsky, Wyston C. Pierre, Annie L. A. Nguyen, Irene Londono, Bela Reiz, Chunxia Zou, Radhika Chakraberty, Gregory A. LodygenskyAbstract:Abstract Background The extension of sepsis encompassing the preterm newborn’s brain is often overlooked due to technical challenges in this highly vulnerable population, yet it leads to substantial long-term neurodevelopmental disabilities. In this study, we demonstrate how neonatal neuroinflammation following postnatal E. coli lipopolysaccharide (LPS) exposure in rat pups results in persistent reduction in sialylation of cerebral glycoproteins. Methods Male Sprague-Dawley rat pups at postnatal day 3 (P3) were injected in the corpus callosum with saline or LPS. Twenty-four hours (P4) or 21 days (P24) following injection, brains were extracted and analyzed for Neuraminidase activity and expression as well as for sialylation of cerebral glycoproteins and glycolipids. Results At both P4 and P24, we detected a significant increase of the acidic Neuraminidase activity in LPS-exposed rats. It correlated with significantly increased Neuraminidase 1 (Neu1) mRNA in LPS-treated brains at P4 and with Neuraminidases 1 and 4 at P24 suggesting that these enzymes were responsible for the rise of Neuraminidase activity. At both P4 and P24, sialylation of N-glycans on brain glycoproteins decreased according to both mass-spectrometry analysis and lectin blotting, but the ganglioside composition remained intact. Finally, at P24, analysis of brain tissues by immunohistochemistry showed that neurons in the upper layers (II–III) of somatosensory cortex had a reduced surface content of polysialic acid. Conclusions Together, our data demonstrate that neonatal LPS exposure results in specific and sustained induction of Neu1 and Neu4, causing long-lasting negative changes in sialylation of glycoproteins on brain cells. Considering the important roles played by sialoglycoproteins in CNS function, we speculate that observed re-programming of the brain sialome constitutes an important part of pathophysiological consequences in perinatal infectious exposure
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inhibitor selectivity of a new class of oseltamivir analogs against viral Neuraminidase over human Neuraminidase enzymes
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Amgad Albohy, Sankar Mohan, Ruixiang Blake Zheng, Mario B Pinto, Christopher W CairoAbstract:The viral Neuraminidase enzyme is an established target for anti-influenza pharmaceuticals. However, viral Neuraminidase inhibitors could have off-target effects due to interactions with native human Neuraminidase enzymes. We report the activity of a series of known inhibitors of the influenza group-1 Neuraminidase enzyme (N1 subtype) against recombinant forms of the human Neuraminidase enzymes NEU3 and NEU4. These inhibitors were designed to take advantage of an additional enzyme pocket (known as the 150-cavity) near the catalytic site of certain viral Neuraminidase subtypes (N1, N4 and N8). We find that these modified derivatives have minimal activity against the human enzymes, NEU3 and NEU4. Two compounds show moderate activity against NEU3, possibly due to alternative binding modes available to these structures. Our results reinforce that recognition of the glycerol side-chain is distinct between the viral and human NEU enzymes, and provide experimental support for improving the selectivity of viral Neuraminidase inhibitors by exploiting the 150-cavity found in certain subtypes of viral Neuraminidases.
Steven J. Gamblin - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of oseltamivir resistant influenza virus Neuraminidase mutants
Nature, 2008Co-Authors: P J Collins, Rupert J. Russell, Lesley F. Haire, Alan Hay, John J. Skehel, Y P Lin, J Liu, Philip A Walker, Stephen R Martin, Steven J. GamblinAbstract:The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre-pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, Neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir (Relenza) are two currently used Neuraminidase inhibitors that were developed using knowledge of the enzyme structure. It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug-resistant mutant viruses that retain viability. However, there have been reports of drug-resistant mutant selection in vitro and from infected humans. We report here the enzymatic properties and crystal structures of Neuraminidase mutants from H5N1-infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 (ref. 7) and H1N1 (ref. 8) viruses with Neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir.
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The structure of H5N1 avian influenza Neuraminidase suggests new opportunities for drug design
Nature, 2006Co-Authors: Rupert J. Russell, Lesley F. Haire, D.j. Stevens, Patrick J. Collins, Yi Pu Lin, G. Michael Blackburn, Alan Hay, Steven J. Gamblin, John J. SkehelAbstract:The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the Neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 Neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 Neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.
Michele R Richards - One of the best experts on this subject based on the ideXlab platform.
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molecular dynamics simulations of viral Neuraminidase inhibitors with the human Neuraminidase enzymes insights into isoenzyme selectivity
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Michele R Richards, Tianlin Guo, Carmanah D Hunter, Christopher W CairoAbstract:Abstract Inhibitors of viral Neuraminidase enzymes have been previously developed as therapeutics. Humans can express multiple forms of Neuraminidase enzymes (NEU1, NEU2, NEU3, NEU4) that share a similar active site and enzymatic mechanism with their viral counterparts. Using a panel of purified human Neuraminidase enzymes, we tested the inhibitory activity of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir, oseltamivir, and peramivir against each of the human isoenzymes. We find that, with the exceptions of DANA and zanamivir, these compounds show generally poor activity against the human Neuraminidase enzymes. To provide insight into the interactions of viral inhibitors with human Neuraminidases, we conducted molecular dynamics simulations using homology models based on coordinates reported for NEU2. Simulations revealed that an organized water is displaced by zanamivir in binding to NEU2 and NEU3 and confirmed the critical importance of engaging the binding pocket of the C7–C9 glycerol sidechain. Our results suggest that compounds designed to target the human Neuraminidases should provide more selective tools for interrogating these enzymes. Furthermore, they emphasize a need for additional structural data to enable structure-based drug design in these systems.
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Selective Inhibitors of Human Neuraminidase 3
2018Co-Authors: Tianlin Guo, Michele R Richards, Alexey V. Pshezhetsky, Chunxia Zou, Philipp Dätwyler, Ekaterina Demina, Ruixiang Zheng, Anne Fougerat, Beat ErnstAbstract:Human Neuraminidases (NEU) are associated with human diseases including cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a Ki of 320 ± 40 nM and a 15-fold selectivity over other human Neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain
Baik Lin Seong - One of the best experts on this subject based on the ideXlab platform.
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structure based design and synthesis of c 1 and c 4 modified analogs of zanamivir as Neuraminidase inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Enguang Feng, Woo Jin Shin, Xuelian Zhu, Jiang Wang, Mingyue Zheng, Jianping Zuo, Xian Liu, Weiliang Zhu, Wei Tang, Baik Lin SeongAbstract:In order to exploit the 430-cavity in the active sites of Neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 Neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and Neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.
Enguang Feng - One of the best experts on this subject based on the ideXlab platform.
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structure based design and synthesis of c 1 and c 4 modified analogs of zanamivir as Neuraminidase inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Enguang Feng, Woo Jin Shin, Xuelian Zhu, Jiang Wang, Mingyue Zheng, Jianping Zuo, Xian Liu, Weiliang Zhu, Wei Tang, Baik Lin SeongAbstract:In order to exploit the 430-cavity in the active sites of Neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 Neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and Neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.
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the 2009 pandemic h1n1 Neuraminidase n1 lacks the 150 cavity in its active site
Nature Structural & Molecular Biology, 2010Co-Authors: Wei Zhang, Christopher J Vavricka, Yi Shi, Jinhua Wei, Enguang Feng, Jingshan Shen, Jilong Chen, Di Liu, Jinghua Yan, Hong LiuAbstract:Influenza A virus Neuraminidase can be classified into groups 1 and 2 on the basis of its primary structure. The main structural feature of group 1 Neuraminidase is an extra cavity in the active site, the 150-cavity. Here we present the crystal structure of Neuraminidase from the 2009 pandemic H1N1 influenza strain. In contrast to other characterized N1 Neuraminidases, which are all members of group 1, 2009 H1N1 Neuraminidase does not have a 150-cavity.