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Your search keyword '"Holly T, Soutter"' showing total 3 results
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3 results on '"Holly T, Soutter"'

1. Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa

Author

Denes Haase, John W. Cuozzo, John Barker, Pia Thommes, Michael Zahn, Avery Hunt, Vasileios Roumpelakis, Ying Zhang, Emily Trimby, Elise Gadouleau, Alain Dorali, Kostas Papadopoulos, Ole A. Andersen, Christoph E. Dumelin, Christel Compper, Michelle Southey, Christopher Lumley, Eric A. Sigel, Paolo A. Centrella, Barbara Mertins, Maisie Holbrow-Wilshaw, Spencer Napier, Adele Faulkner, Magali Dejob, Timothy Gorman, Alastair L Parkes, Boudewijn Dejonge, Thomas Krulle, Ricky Cain, Jennifer Williams, Boer Deng, Olivier Barbeau, Anthony D. Keefe, Sian Evans, David F. Corbett, Donnya Etheridge, Daniel B. Stein, Ryan M Dominic, Dawn M. Troast, Xianfu Li, Rajesh Odedra, Matthew A. Clark, Anthony P Dickie, Holly T Soutter, Kate Spear, and Angelo Sanzone

Subjects
Biochemistry, Pseudomonas aeruginosa, Chemistry, Acyltransferase, Drug Discovery, medicine, Molecular Medicine, Potency, Antimicrobial, medicine.disease_cause, IC50, UDP-N-acetylglucosamine acyltransferase, Escherichia coli
Abstract

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.

Published
2021

2. Discovery of Novel UDP

Author

M Dominic, Ryan, Alastair L, Parkes, David, Corbett, Anthony P, Dickie, Michelle, Southey, Ole A, Andersen, Daniel B, Stein, Olivier R, Barbeau, Angelo, Sanzone, Pia, Thommes, John, Barker, Ricky, Cain, Christel, Compper, Magali, Dejob, Alain, Dorali, Donnya, Etheridge, Sian, Evans, Adele, Faulkner, Elise, Gadouleau, Timothy, Gorman, Denes, Haase, Maisie, Holbrow-Wilshaw, Thomas, Krulle, Xianfu, Li, Christopher, Lumley, Barbara, Mertins, Spencer, Napier, Rajesh, Odedra, Kostas, Papadopoulos, Vasileios, Roumpelakis, Kate, Spear, Emily, Trimby, Jennifer, Williams, Michael, Zahn, Anthony D, Keefe, Ying, Zhang, Holly T, Soutter, Paolo A, Centrella, Matthew A, Clark, John W, Cuozzo, Christoph E, Dumelin, Boer, Deng, Avery, Hunt, Eric A, Sigel, Dawn M, Troast, and Boudewijn L M, DeJonge

Subjects
Structure-Activity Relationship, Molecular Structure, Drug Discovery, Drug Resistance, Bacterial, Pseudomonas aeruginosa, Escherichia coli, Microbial Sensitivity Tests, Enzyme Inhibitors, Crystallography, X-Ray, Acyltransferases, Anti-Bacterial Agents
Abstract

This study describes a novel series of UDP

Published
2021

3. Agonists and Antagonists of Protease-Activated Receptor 2 Discovered within a DNA-Encoded Chemical Library Using Mutational Stabilization of the Target

Author

Eric A. Sigel, Paolo A. Centrella, Ying Zhang, Stefan Geschwindner, Niek Dekker, Sevan Habeshian, Matthew A. Clark, Cédric Fiez-Vandal, Dawn M. Troast, John W. Cuozzo, Marie-Aude Guié, Linda Sundström, Christoph E. Dumelin, Giselle R. Wiggin, Jing Zhang, Robert M. Cooke, Kaan Certel, Dean G. Brown, Arjan Snijder, Giles A. Brown, Anthony D. Keefe, Oliver Schlenker, Andrew D. Ferguson, and Holly T Soutter

Subjects
0301 basic medicine, Agonist, Structural similarity, medicine.drug_class, Allosteric regulation, Mutant, Ligands, 01 natural sciences, Biochemistry, Cell Line, Receptors, G-Protein-Coupled, Analytical Chemistry, Chemical library, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, medicine, Humans, Receptor, PAR-2, Receptor, Protease-activated receptor 2, G protein-coupled receptor, 010405 organic chemistry, Proteins, DNA, 0104 chemical sciences, HEK293 Cells, 030104 developmental biology, chemistry, Mutation, Molecular Medicine, Allosteric Site, Biotechnology
Abstract

The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2). Using a thermo-stabilized mutant of PAR2, we conducted affinity selection using our >100-billion-compound DNA-encoded library. We observed a number of putative ligands enriched upon selection, and subsequent cellular profiling revealed these ligands to comprise both agonists and antagonists. The agonist series shared structural similarity with known agonists. The antagonists were shown to bind in a novel allosteric binding site on the PAR2 protein. This report serves to demonstrate that cell-free affinity selection against GPCRs can be achieved with mutant stabilized protein targets.

Published
2018

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