The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Mark Von Itzstein - One of the best experts on this subject based on the ideXlab platform.
-
A sialosyl sulfonate as a potent inhibitor of influenza Virus replication
Organic & biomolecular chemistry, 2017Co-Authors: Ádám Hadházi, Jeffrey Clifford Dyason, Benjamin Bailly, Robin J. Thomson, Anikó Borbás, Mauro Pascolutti, Mark Von ItzsteinAbstract:A new direction for influenza Virus Sialidase inhibitor development was identified using a sulfonate congener of 2-deoxy-2-β-H N-acetylneuraminic acid. Sialosyl sulfonates can be synthesised efficiently in four steps from N-acetylneuraminic acid via a microwave assisted decarboxylation. The presence of the sulfonate group significantly increases inhibition of influenza Virus Sialidase and viral infection when compared to the carboxylate congener, and also to the benchmark Sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en.
-
influenza Virus Sialidase
2015Co-Authors: Mark Von ItzsteinAbstract:Influenza Virus Sialidase , Influenza Virus Sialidase , کتابخانه مرکزی دانشگاه علوم پزشکی تهران
-
Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza Virus Sialidase 150-loop.
Bioorganic & medicinal chemistry, 2013Co-Authors: Santosh Rudrawar, Jeffrey Clifford Dyason, Andrea Maggioni, Robin J. Thomson, Mark Von ItzsteinAbstract:Novel 3,4-disubstituted-Neu5Ac2en derivatives have been synthesised to probe the open 150-loop conformation of influenza Virus Sialidases. Both equatorially and axially (epi) substituted C4 amino and guanidino 3-(p-tolyl)allyl-Neu5Ac2en derivatives were prepared, via the 4-epi-hydroxy derivative. The equatorially-substituted 4-amino derivative showed low micromolar inhibition of both group-1 (pdm09 H1N1) and group-2 (pdm57 H2N2) Sialidases, and provides the first in vitro evidence that a group-2 Sialidase may exhibit 150-loop flexibility.
-
Exploring the interactions of unsaturated glucuronides with influenza Virus Sialidase.
Journal of medicinal chemistry, 2012Co-Authors: Beenu Bhatt, Jeffrey Clifford Dyason, Philip S Kerry, Rupert J Russell, Robin J. Thomson, Raphael Böhm, Mark Von ItzsteinAbstract:A series of C3 O-functionalized 2-acetamido-2-deoxy-Δ4-β-d-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza Virus Sialidase active site. In complex with...
-
Novel carbohydrate-based inhibitors that target influenza A Virus Sialidase
Chembiomolecular Science, 2012Co-Authors: Mark Von ItzsteinAbstract:Influenza Virus continues to cause significant morbidity and mortality despite the fact that both anti-influenza viral drugs and vaccines to the current circulating strains are available [1, 2]. In terms of anti-influenza drug development, the surface-oriented viral enzyme Sialidase (neuraminidase, NA), which plays a major role in the Virus life cycle by facilitating release of Virus progeny from the infected cell [3], has proven a successful target for the development of clinically useful drugs [4, 5]. Potent and selective inhibitors of the viral Sialidase, such as zanamivir (1, Relenza) and oseltamivir carboxylate (OC, 2; the active form of oseltamivir 3, Tamiflu), the two widely used anti-influenza drugs, efficiently block viral Sialidase activity resulting in Virus progeny remaining clumped at the infected cell’s surface [6] and, consequently, limitation of the spread of infection. The phenomenon of resistance development to drugs-in-use, however, is a continuing issue [7], and applies to both zanamivir and oseltamivir. Oseltamivir, the most used anti-influenza drug, has suffered significant loss of efficacy as a result of drug resistance during the past 4 years [7].
Paul W. Smith - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis of a tetrasubstituted bicyclo [2.2.2] octane as a potential inhibitor of influenza Virus Sialidase.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul W. Smith, Naimisha Trivedi, Peter D. Howes, Steven L. Sollis, George Rahim, Richard C. Bethell, Sean M. LynnAbstract:A novel synthesis of the bicyclo [2.2.2] octane ring system has been achieved utilising a tandem Henry cyclisation as the key stage. This chemistry has been employed in the synthesis of a potential inhibitor of influenza Virus Sialidase.
-
Sialidase inhibitors related to zanamivir: synthesis and biological evaluation of 4H-pyran 6-ether and ketone.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul W. Smith, Naimisha Trivedi, Peter D. Howes, Steven L. Sollis, J. Ed Robinson, Derek N. Evans, Richard C. BethellAbstract:Synthesis of 5R-Acetamido-4S-amino-4H-pyran-6R-O-(1-ethyl)propyl and 6R-(1-oxo-2-ethyl)butyl 2-carboxylic acids (4 and 5) and their evaluation as inhibitors of influenza Virus Sialidase is described. Both compounds showed good inhibitory activity with marked selectivity for influenza A Sialidase.
-
Synthesis of tetrasubstituted bicyclo[3.2.1]octenes as potential inhibitors of influenza Virus Sialidase.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul Spencer Jones, Paul W. Smith, Peter D. Howes, George W. Hardy, Richard J. Upton, Richard C. BethellAbstract:Several racemic bicyclo[3.2.1]octene derivatives have been synthesised and evaluated as inhibitors of influenza Virus Sialidases. The 5-acetamido-bicyclo[3.2.1]octenol 4 showed modest activity against influenza A and B Virus Sialidases.
-
Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza Virus Sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and Sialidase from influenza Virus types A and B
Journal of medicinal chemistry, 1998Co-Authors: Neil R. Taylor, Paul W. Smith, Peter D. Howes, Steven L. Sollis, Anne Cleasby, Onkar M. P. Singh, Tadeusz Skarzynski, Alan J. Wonacott, Peter C. Cherry, Richard C. BethellAbstract:The first paper in this series (see previous article) described structure−activity studies of carboxamide analogues of zanamivir binding to influenza Virus Sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein−ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In Sialidase from type A Virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, ...
-
Sialidase as a target for inhibitors of influenza Virus replication.
Expert opinion on investigational drugs, 1997Co-Authors: Richard C. Bethell, Paul W. SmithAbstract:Structure-based drug design has led to the identification of potent and selective inhibitors of influenza Virus Sialidase, which have antiviral activity in vitro and in experimental animal models of influenza infection. Clinical studies with one such Sialidase inhibitor, zanamivir, have shown this compound to be a safe and effective therapy for influenza infections in man. Passage of influenza Viruses in the presence of zanamivir in vitro has been shown to result in the selection of Viruses with reduced sensitivity to this drug. To date, however, there have been no reports of the isolation of zanamivir-resistant Viruses during clinical studies of this compound. Further application of structure-based drug design is yielding novel classes of potent inhibitors of influenza Virus Sialidase.
Robin J. Thomson - One of the best experts on this subject based on the ideXlab platform.
-
A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity.
ChemMedChem, 2018Co-Authors: Ádám Hadházi, Jeffrey Clifford Dyason, Benjamin Bailly, Andrea Maggioni, Gael Martin, Larissa Dirr, Robin J. Thomson, George F. Gao, Anikó BorbásAbstract:Influenza Virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti-influenza agents is the Virus surface protein Sialidase. In the current study, we have discovered a highly potent inhibitor of influenza Virus Sialidase, based on a novel sialosyl sulfonate template. The synthesised 3-guanidino sialosyl α-sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template binds within the Sialidase active site in a 1 C4 chair conformation. The C1-sulfonate moiety forms crucial and strong-binding interactions with the active site's triarginyl cluster, while the 3-guanidino moiety interacts significantly with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti-influenza Virus drug development.
-
A sialosyl sulfonate as a potent inhibitor of influenza Virus replication
Organic & biomolecular chemistry, 2017Co-Authors: Ádám Hadházi, Jeffrey Clifford Dyason, Benjamin Bailly, Robin J. Thomson, Anikó Borbás, Mauro Pascolutti, Mark Von ItzsteinAbstract:A new direction for influenza Virus Sialidase inhibitor development was identified using a sulfonate congener of 2-deoxy-2-β-H N-acetylneuraminic acid. Sialosyl sulfonates can be synthesised efficiently in four steps from N-acetylneuraminic acid via a microwave assisted decarboxylation. The presence of the sulfonate group significantly increases inhibition of influenza Virus Sialidase and viral infection when compared to the carboxylate congener, and also to the benchmark Sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en.
-
Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza Virus Sialidase 150-loop.
Bioorganic & medicinal chemistry, 2013Co-Authors: Santosh Rudrawar, Jeffrey Clifford Dyason, Andrea Maggioni, Robin J. Thomson, Mark Von ItzsteinAbstract:Novel 3,4-disubstituted-Neu5Ac2en derivatives have been synthesised to probe the open 150-loop conformation of influenza Virus Sialidases. Both equatorially and axially (epi) substituted C4 amino and guanidino 3-(p-tolyl)allyl-Neu5Ac2en derivatives were prepared, via the 4-epi-hydroxy derivative. The equatorially-substituted 4-amino derivative showed low micromolar inhibition of both group-1 (pdm09 H1N1) and group-2 (pdm57 H2N2) Sialidases, and provides the first in vitro evidence that a group-2 Sialidase may exhibit 150-loop flexibility.
-
Exploring the interactions of unsaturated glucuronides with influenza Virus Sialidase.
Journal of medicinal chemistry, 2012Co-Authors: Beenu Bhatt, Jeffrey Clifford Dyason, Philip S Kerry, Rupert J Russell, Robin J. Thomson, Raphael Böhm, Mark Von ItzsteinAbstract:A series of C3 O-functionalized 2-acetamido-2-deoxy-Δ4-β-d-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza Virus Sialidase active site. In complex with...
-
The Development of Carbohydrate-Based Influenza Virus Sialidase Inhibitors
Influenza Virus Sialidase - A Drug Discovery Target, 2011Co-Authors: Robin J. Thomson, Mark Von ItzsteinAbstract:This chapter presents a review of the development of influenza Virus Sialidase inhibitors based on a carbohydrate scaffold, predominantly that of the natural ‘ligand’ of the enzyme, N-acetylneuraminic acid (Neu5Ac). These inhibitors include hydrolytically stable substrate-like compounds, product mimics, and transition-state-like compounds. The major focus of the chapter, reflecting the most intensively researched area of inhibitor development, is on the use of the dihydropyran scaffold of the 2,3-unsaturated-Neu5Ac derivative, Neu5Ac2en, a putative transition state mimic. Structure-based drug design targeting conserved residues of the Sialidase active site using this template leading to the development of the potent and selective inhibitor, and anti-influenza drug, zanamivir (Relenza™), as well as subsequent developments towards next generation inhibitors, are discussed.
Jeffrey Clifford Dyason - One of the best experts on this subject based on the ideXlab platform.
-
A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity.
ChemMedChem, 2018Co-Authors: Ádám Hadházi, Jeffrey Clifford Dyason, Benjamin Bailly, Andrea Maggioni, Gael Martin, Larissa Dirr, Robin J. Thomson, George F. Gao, Anikó BorbásAbstract:Influenza Virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti-influenza agents is the Virus surface protein Sialidase. In the current study, we have discovered a highly potent inhibitor of influenza Virus Sialidase, based on a novel sialosyl sulfonate template. The synthesised 3-guanidino sialosyl α-sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template binds within the Sialidase active site in a 1 C4 chair conformation. The C1-sulfonate moiety forms crucial and strong-binding interactions with the active site's triarginyl cluster, while the 3-guanidino moiety interacts significantly with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti-influenza Virus drug development.
-
A sialosyl sulfonate as a potent inhibitor of influenza Virus replication
Organic & biomolecular chemistry, 2017Co-Authors: Ádám Hadházi, Jeffrey Clifford Dyason, Benjamin Bailly, Robin J. Thomson, Anikó Borbás, Mauro Pascolutti, Mark Von ItzsteinAbstract:A new direction for influenza Virus Sialidase inhibitor development was identified using a sulfonate congener of 2-deoxy-2-β-H N-acetylneuraminic acid. Sialosyl sulfonates can be synthesised efficiently in four steps from N-acetylneuraminic acid via a microwave assisted decarboxylation. The presence of the sulfonate group significantly increases inhibition of influenza Virus Sialidase and viral infection when compared to the carboxylate congener, and also to the benchmark Sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en.
-
Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza Virus Sialidase 150-loop.
Bioorganic & medicinal chemistry, 2013Co-Authors: Santosh Rudrawar, Jeffrey Clifford Dyason, Andrea Maggioni, Robin J. Thomson, Mark Von ItzsteinAbstract:Novel 3,4-disubstituted-Neu5Ac2en derivatives have been synthesised to probe the open 150-loop conformation of influenza Virus Sialidases. Both equatorially and axially (epi) substituted C4 amino and guanidino 3-(p-tolyl)allyl-Neu5Ac2en derivatives were prepared, via the 4-epi-hydroxy derivative. The equatorially-substituted 4-amino derivative showed low micromolar inhibition of both group-1 (pdm09 H1N1) and group-2 (pdm57 H2N2) Sialidases, and provides the first in vitro evidence that a group-2 Sialidase may exhibit 150-loop flexibility.
-
synthesis and evaluation of novel 3 c alkylated neu5ac2en derivatives as probes of influenza Virus Sialidase 150 loop flexibility
Organic and Biomolecular Chemistry, 2012Co-Authors: Santosh Rudrawar, Jeffrey Clifford Dyason, Marieanne Rameixwelti, Faith Josephine Rose, Philip S Kerry, Andrea Maggioni, Sylvie Van Der WerfAbstract:Novel 3-C-alkylated-Neu5Ac2en derivatives have been designed to target the expanded active site cavity of influenza Virus Sialidases with an open 150-loop, currently seen in X-ray crystal structures of influenza A Virus group-1 (N1, N4, N5, N8), but not group-2 (N2, N9), Sialidases. The compounds show selectivity for inhibition of H5N1 and pdm09 H1N1 Sialidases over an N2 Sialidase, providing evidence of the relative 150-loop flexibility of these Sialidases. In a complex with N8 Sialidase, the C3 substituent of 3-phenylally-Neu5Ac2en occupies the 150-cavity while the central ring and the remaining substituents bind the active site as seen for the unsubstituted template. This new class of inhibitors, which can ‘trap’ the open 150-loop form of the Sialidase, should prove useful as probes of 150-loop flexibility.
-
Exploring the interactions of unsaturated glucuronides with influenza Virus Sialidase.
Journal of medicinal chemistry, 2012Co-Authors: Beenu Bhatt, Jeffrey Clifford Dyason, Philip S Kerry, Rupert J Russell, Robin J. Thomson, Raphael Böhm, Mark Von ItzsteinAbstract:A series of C3 O-functionalized 2-acetamido-2-deoxy-Δ4-β-d-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza Virus Sialidase active site. In complex with...
Richard C. Bethell - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis of a tetrasubstituted bicyclo [2.2.2] octane as a potential inhibitor of influenza Virus Sialidase.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul W. Smith, Naimisha Trivedi, Peter D. Howes, Steven L. Sollis, George Rahim, Richard C. Bethell, Sean M. LynnAbstract:A novel synthesis of the bicyclo [2.2.2] octane ring system has been achieved utilising a tandem Henry cyclisation as the key stage. This chemistry has been employed in the synthesis of a potential inhibitor of influenza Virus Sialidase.
-
Sialidase inhibitors related to zanamivir: synthesis and biological evaluation of 4H-pyran 6-ether and ketone.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul W. Smith, Naimisha Trivedi, Peter D. Howes, Steven L. Sollis, J. Ed Robinson, Derek N. Evans, Richard C. BethellAbstract:Synthesis of 5R-Acetamido-4S-amino-4H-pyran-6R-O-(1-ethyl)propyl and 6R-(1-oxo-2-ethyl)butyl 2-carboxylic acids (4 and 5) and their evaluation as inhibitors of influenza Virus Sialidase is described. Both compounds showed good inhibitory activity with marked selectivity for influenza A Sialidase.
-
Synthesis of tetrasubstituted bicyclo[3.2.1]octenes as potential inhibitors of influenza Virus Sialidase.
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Paul Spencer Jones, Paul W. Smith, Peter D. Howes, George W. Hardy, Richard J. Upton, Richard C. BethellAbstract:Several racemic bicyclo[3.2.1]octene derivatives have been synthesised and evaluated as inhibitors of influenza Virus Sialidases. The 5-acetamido-bicyclo[3.2.1]octenol 4 showed modest activity against influenza A and B Virus Sialidases.
-
Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza Virus Sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and Sialidase from influenza Virus types A and B
Journal of medicinal chemistry, 1998Co-Authors: Neil R. Taylor, Paul W. Smith, Peter D. Howes, Steven L. Sollis, Anne Cleasby, Onkar M. P. Singh, Tadeusz Skarzynski, Alan J. Wonacott, Peter C. Cherry, Richard C. BethellAbstract:The first paper in this series (see previous article) described structure−activity studies of carboxamide analogues of zanamivir binding to influenza Virus Sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein−ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In Sialidase from type A Virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, ...
-
Sialidase as a target for inhibitors of influenza Virus replication.
Expert opinion on investigational drugs, 1997Co-Authors: Richard C. Bethell, Paul W. SmithAbstract:Structure-based drug design has led to the identification of potent and selective inhibitors of influenza Virus Sialidase, which have antiviral activity in vitro and in experimental animal models of influenza infection. Clinical studies with one such Sialidase inhibitor, zanamivir, have shown this compound to be a safe and effective therapy for influenza infections in man. Passage of influenza Viruses in the presence of zanamivir in vitro has been shown to result in the selection of Viruses with reduced sensitivity to this drug. To date, however, there have been no reports of the isolation of zanamivir-resistant Viruses during clinical studies of this compound. Further application of structure-based drug design is yielding novel classes of potent inhibitors of influenza Virus Sialidase.
