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1. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection

Author

Philippe Karoyan, Vincent Vieillard, Luis Gómez-Morales, Estelle Odile, Amélie Guihot, Charles-Edouard Luyt, Alexis Denis, Pascal Grondin, and Olivier Lequin

Subjects
Biology (General), QH301-705.5
Abstract

Karoyan et al. present a method to inhibit SARS-CoV-2 by means of a peptide-mimic approach. They design a series of peptides mimicking the N-terminal helix of hACE2 protein and their best peptide-mimic blocks SARS-CoV-2 human pulmonary cell infection with an IC50 in nanomolar range.

Published
2021
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2. Development of a small molecule that corrects misfolding and increases secretion of Z α1‐antitrypsin

Author

David A Lomas, James A Irving, Christopher Arico‐Muendel, Svetlana Belyanskaya, Andrew Brewster, Murray Brown, Chun‐wa Chung, Hitesh Dave, Alexis Denis, Nerina Dodic, Anthony Dossang, Peter Eddershaw, Diana Klimaszewska, Imran Haq, Duncan S Holmes, Jonathan P Hutchinson, Alistair M Jagger, Toral Jakhria, Emilie Jigorel, John Liddle, Ken Lind, Stefan J Marciniak, Jeff Messer, Margaret Neu, Allison Olszewski, Adriana Ordonez, Riccardo Ronzoni, James Rowedder, Martin Rüdiger, Steve Skinner, Kathrine J Smith, Rebecca Terry, Lionel Trottet, Iain Uings, Steve Wilson, Zhengrong Zhu, and Andrew C Pearce

Subjects
emphysema, liver disease, protein misfolding, small molecule corrector, α1‐antitrypsin deficiency, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.

Published
2021
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4. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection

Author

Alexis Denis, Olivier Lequin, Amélie Guihot, Pascal Grondin, Philippe Karoyan, Luis Gómez-Morales, Charles-Edouard Luyt, Vincent Vieillard, Estelle Odile, Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de cardiologie [CHU Pitié-Salpêtrière], Laboratoires Oncodesign [Villebon-sur-Yvette], Centre de Recherches François Hyafil [Villebon-sur-Yvette], Gestionnaire, HAL Sorbonne Université 5, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Oncodesign [Dijon], Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, viruses, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Peptide, Virus Replication, Protein Structure, Secondary, Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Protein structure, Humans, Amino Acid Sequence, Biology (General), Binding site, skin and connective tissue diseases, Receptor, Peptide sequence, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, SARS-CoV-2, Circular Dichroism, fungi, COVID-19, respiratory tract diseases, 3. Good health, Cell biology, body regions, 030104 developmental biology, chemistry, Viral infection, Cell culture, Spike Glycoprotein, Coronavirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Angiotensin-Converting Enzyme 2, Structure-based drug design, Peptides, General Agricultural and Biological Sciences, Glycoprotein, 030217 neurology & neurosurgery, Protein Binding
Abstract

In light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site, exhibiting a high helical folding propensity in aqueous solution. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19)., Karoyan et al. present a method to inhibit SARS-CoV-2 by means of a peptide-mimic approach. They design a series of peptides mimicking the N-terminal helix of hACE2 protein and their best peptide-mimic blocks SARS-CoV-2 human pulmonary cell infection with an IC50 in nanomolar range.

Published
2021
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5. The development of highly potent and selective small molecule correctors of Z α

Author

John, Liddle, Andrew C, Pearce, Christopher, Arico-Muendel, Svetlana, Belyanskaya, Andrew, Brewster, Murray, Brown, Chun-Wa, Chung, Alexis, Denis, Nerina, Dodic, Anthony, Dossang, Peter, Eddershaw, Diana, Klimaszewska, Imran, Haq, Duncan S, Holmes, Alistair, Jagger, Toral, Jakhria, Emilie, Jigorel, Ken, Lind, Jeff, Messer, Margaret, Neu, Allison, Olszewski, Riccardo, Ronzoni, James, Rowedder, Martin, Rüdiger, Steve, Skinner, Kathrine J, Smith, Lionel, Trottet, Iain, Uings, Zhengrong, Zhu, James A, Irving, and David A, Lomas

Subjects
Models, Molecular, Protein Folding, Drug Development, Protein Conformation, Drug Design, alpha 1-Antitrypsin, Drug Evaluation, Preclinical, Hepatocytes, Humans, Crystallization, Endoplasmic Reticulum, Gene Library
Abstract

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α

Published
2020

6. Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection

Author

Vincent Vieillard, Olivier Lequin, Charles-Edouard Luyt, Alexis Denis, Amélie Guihot, Philippe Karoyan, Pascal Grondin, Estelle Odile, and Luis Gómez-Morales

Subjects
chemistry.chemical_classification, medicine.anatomical_structure, Chemistry, Cell, Angiotensin-converting enzyme 2, medicine, Peptide, Binding site, Receptor, Glycoprotein, IC50, Virus, Cell biology
Abstract

In the light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site and have a high helical folding propensity in aqueous solution. Our best peptide mimics bind to the virus spike protein with high affinity and are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range. These first in class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19).

Published
2020
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7. Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

Author

Stefan J. Marciniak, Martin Rüdiger, Hitesh Dave, Jonathan P. Hutchinson, Margaret Neu, Anthony Dossang, Riccardo Ronzoni, Lionel Trottet, Adriana Ordóñez, Chun-wa Chung, Christopher C. Arico-Muendel, Alexis Denis, Allison Olszewski, Andrew C. Pearce, Ken Lind, Peter Eddershaw, Andrew Brewster, Rebecca Terry, Jeffrey A. Messer, John Liddle, Iain Uings, Emilie Jigorel, James A. Irving, Nerina Dodic, Zhengrong Zhu, Kathrine J. Smith, Duncan S. Holmes, Steve Skinner, Steve Wilson, David A. Lomas, Diana Klimaszewska, James E. Rowedder, Murray J. B. Brown, Alistair M. Jagger, Toral Jakhria, Imran Haq, and Svetlana L. Belyanskaya

Subjects
Genetically modified mouse, Mutation, Chemistry, Endoplasmic reticulum, Mutant, medicine, Secretion, medicine.disease_cause, Small molecule, Intracellular, In vitro, Cell biology
Abstract

Severe α1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z α1-antitrypsin. The lead compound blocks Z α1-antitrypsin polymerisationin vitro, reduces intracellular polymerisation and increases the secretion of Z α1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that ‘mutation ameliorating’ small molecules are a viable approach to treat protein conformational diseases.

Published
2020
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8. The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

Author

Lionel Trottet, Martin Rüdiger, Anthony Dossang, Alexis Denis, David A. Lomas, James A. Irving, Andrew C. Pearce, Andrew Brewster, John Liddle, Zhengrong Zhu, Peter Eddershaw, James E. Rowedder, Kathrine J. Smith, Chun-wa Chung, Ken Lind, Christopher C. Arico-Muendel, Jeffrey A. Messer, Allison Olszewski, Diana Klimaszewska, Murray J. B. Brown, Nerina Dodic, Duncan S. Holmes, Imran Haq, Alistair M. Jagger, Toral Jakhria, Steve Skinner, Margaret Neu, Riccardo Ronzoni, Emilie Jigorel, Iain Uings, and Svetlana L. Belyanskaya

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, 010405 organic chemistry, Chemistry, Endoplasmic reticulum, Organic Chemistry, Clinical Biochemistry, Mutant, Pharmaceutical Science, 01 natural sciences, Biochemistry, Small molecule, digestive system diseases, respiratory tract diseases, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, α1 antitrypsin, Drug Discovery, Biophysics, Molecular Medicine, Structure based, Molecular Biology, Intracellular
Abstract

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Published
2021
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9. The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis

Author

Scott P. Webster, Andrew McBride, Sandeep Pal, Ann Louise Walker, Duncan S. Holmes, Michael M. Hann, Jon P. Hutchinson, Lionel Trottet, Damian J. Mole, Anne Marie Jeanne Bouillot, Carl Haslam, John Liddle, Olivier Mirguet, Benjamin Beaufils, Paul Rowland, Margaret Binnie, Alexis Denis, Christopher G. Mowat, Michael Kranz, and Iain Uings

Subjects
0301 basic medicine, Indazoles, Clinical Biochemistry, Pharmaceutical Science, Pharmacology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Kynurenine 3-Monooxygenase, In vivo, Drug Discovery, medicine, Journal Article, Animals, Humans, Potency, Enzyme Inhibitors, Molecular Biology, Kynurenine, Benzoxazoles, Chemistry, Organic Chemistry, Tryptophan, Monooxygenase, medicine.disease, Rats, HEK293 Cells, 030104 developmental biology, Pancreatitis, Molecular Medicine, Acute pancreatitis, Lead compound
Abstract

A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.

Published
2017
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10. Corrigendum to ‘Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors’ [Bioorg. Med. Chem. Lett. 29 (2019) 126675]

Author

Andrew C. Pearce, Alexis Denis, Ann Louise Walker, Pam Nassau, Emma V. Edgar, Anne Marie Jeanne Bouillot, Lionel Trottet, Yichen Wang, Alain Hovnanian, Oxana Polyakova, Marie-Hélène Fouchet, Alexandre Moquette, Duncan S. Holmes, Alan R. Ferrie, Alain Laroze, Kathrine J. Smith, John Liddle, Ryan P. Bingham, Pamela Thomas, and James H. Thorpe

Subjects
Covalent bond, Chemistry, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Kallikrein, Molecular Biology, Biochemistry
Published
2020
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11. Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors

Author

Pam Nassau, Andrew C. Pearce, Lionel Trottet, Ann Louise Walker, Alexis Denis, Duncan S. Holmes, Pamela Thomas, Alan R. Ferrie, Kathrine J. Smith, Alexandre Moquette, James H. Thorpe, Emma V. Edgar, Anne Marie Jeanne Bouillot, Marie-Hélène Fouchet, Alain Laroze, John Liddle, Ryan P. Bingham, Alain Hovnanian, Oxana Polyakova, and Yichen Wang

Subjects
Models, Molecular, Proteases, Serine Proteinase Inhibitors, medicine.medical_treatment, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, 01 natural sciences, Biochemistry, Structure-Activity Relationship, Isomerism, Drug Discovery, Hydrolase, medicine, Humans, Netherton syndrome, Amino Acid Sequence, Molecular Biology, Binding Sites, Protease, Molecular Structure, integumentary system, 010405 organic chemistry, Chemistry, Organic Chemistry, KLK5, Kallikrein, medicine.disease, Benzamidines, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, LEKTI, Netherton Syndrome, Covalent bond, Mutation, Serine Peptidase Inhibitor Kazal-Type 5, Molecular Medicine, Kallikreins, Protein Binding
Abstract

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Published
2019
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12. Corrigendum: A unique peptide deformylase platform to rationally design and challenge novel active compounds

Author

Thierry Meinnel, Karim Hamiche, Rodolphe Alves de Sousa, Carmela Giglione, Laure Maigre, Alexis Denis, Sonia Fieulaine, Jean-Michel Bolla, Isabelle Artaud, Mickael Alimi, Abbass Taleb, Jean-Marie Pagès, Interactions et mécanismes d’assemblage des protéines et des peptides (IMAPP), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA)-Aix Marseille Université (AMU), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), GlaxoSmithKline, Glaxo Smith Kline, Maturation des proteines, destinée cellulaire et thérapeutique (PROMTI), Département Biologie des Génomes (DBG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), SERRE, Marie-Claude, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)

Subjects
0303 health sciences, Multidisciplinary, Computer science, Published Erratum, [SDV]Life Sciences [q-bio], Computational biology, Corrigenda, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Peptide deformylase, 0302 clinical medicine, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

Published
2017
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13. A unique peptide deformylase platform to rationally design and challenge novel active compounds

Author

Karim Hamiche, Alexis Denis, Carmela Giglione, Laure Maigre, Rodolphe Alves de Sousa, Mickael Alimi, Jean-Michel Bolla, Isabelle Artaud, Sonia Fieulaine, Thierry Meinnel, Abbass Taleb, Jean-Marie Pagès, Interactions et mécanismes d’assemblage des protéines et des peptides (IMAPP), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GlaxoSmithKline, Glaxo Smith Kline, Maturation des proteines, destinée cellulaire et thérapeutique (PROMTI), Département Biologie des Génomes (DBG), Interactions et mécanismes d’assemblage des protéines et des peptides ( IMAPP ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Transporteurs membranaires, chimioresistance et drug-design ( TMCD2 ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maturation des proteines, destinée cellulaire et thérapeutique ( PROMTI ), Département Biologie des Génomes ( DBG ), and GRECH, Cécile

Subjects
0301 basic medicine, Multidisciplinary, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Relationship analysis, fungi, Computational biology, Biology, medicine.disease_cause, Ligand (biochemistry), Antimicrobial, Bioinformatics, Article, [SDV] Life Sciences [q-bio], Multiple drug resistance, body regions, 03 medical and health sciences, Peptide deformylase, 030104 developmental biology, Streptococcus agalactiae, nervous system, Hydrolase, medicine
Abstract

Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

Published
2016
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14. From Triclosan toward the Clinic: Discovery of Nonbiocidal, Potent FabI Inhibitors for the Treatment of Resistant Bacteria

Author

Cédric Raymond, François Moreau, Laure Prouvensier, Jean-Marie Genevard, Yannick Bonvin, Lionel Durant, Laëtitia Peltier, Armelle Walton, Coralie Soulama-Mouze, Stéphanie Floquet, Elodie Drocourt, Vincent Gerusz, Mayalen Oxoby, Sonia Escaich, Géraldine LeFralliec, Vanessa Sam-Sambo, Vanida Vongsouthi, Nicolas Desroy, Marc Saccomani, Chrystelle Oliveira, Sophia Briet, Alexis Denis, and Fabien Faivre

Subjects
Models, Molecular, Gram-negative bacteria, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, Biology, Pharmacology, Microbiology, Structure-Activity Relationship, chemistry.chemical_compound, Dogs, Drug Resistance, Multiple, Bacterial, Gram-Negative Bacteria, Drug Discovery, Animals, Humans, Cells, Cultured, Molecular Structure, Phenyl Ethers, biology.organism_classification, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), Preclinical data, Triclosan, Rats, Resistant bacteria, chemistry, Benzamides, Anti-Infective Agents, Local, Molecular Medicine
Abstract

In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.

Published
2012
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15. Towards Gram-positive antivirulence drugs: New inhibitors of Streptococcus agalactiae Stk1

Author

Lionel Durant, Sonia Escaich, Jean-Marie Genevard, Alexis Denis, François Moreau, Mayalen Oxoby, Vincent Gerusz, and Vanida Vongsouthi

Subjects
Gram-positive bacteria, Clinical Biochemistry, Pharmaceutical Science, Virulence, Protein Serine-Threonine Kinases, Gram-Positive Bacteria, medicine.disease_cause, Biochemistry, Article, Streptococcus agalactiae, Microbiology, Structure-Activity Relationship, Drug Discovery, medicine, Urea, Structure–activity relationship, Molecular Biology, Antibacterial agent, chemistry.chemical_classification, biology, Organic Chemistry, biology.organism_classification, Streptococcaceae, Anti-Bacterial Agents, Enzyme, chemistry, Molecular Medicine, Bacteria
Abstract

Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 < 60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 < 400 nM) with a 5.4-fold selectivity over haspin was also identified.

Published
2010
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16. Towards Gram-negative antivirulence drugs: New inhibitors of HldE kinase

Author

Alexis Denis, Nicolas Desroy, Sonia Escaich, Lionel Durant, Vincent Gerusz, Vanida Vongsouthi, Géraldine Le Fralliec, François Moreau, Stéphanie Floquet, and Sophia Briet

Subjects
Gram-negative bacteria, Lipopolysaccharide, Membrane permeability, Molecular Sequence Data, Clinical Biochemistry, Pharmaceutical Science, Heptose, Virulence, Biochemistry, Inhibitory Concentration 50, Structure-Activity Relationship, chemistry.chemical_compound, Multienzyme Complexes, Gram-Negative Bacteria, Drug Discovery, Escherichia coli, Humans, Structure–activity relationship, Phosphofructokinase 2, Amino Acid Sequence, Molecular Biology, Antibacterial agent, chemistry.chemical_classification, Sequence Homology, Amino Acid, biology, Organic Chemistry, Heptoses, biology.organism_classification, Nucleotidyltransferases, Anti-Bacterial Agents, Kinetics, Phosphotransferases (Alcohol Group Acceptor), chemistry, Molecular Medicine, Sequence Alignment
Abstract

Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relationship of this series of inhibitors led to highly potent compounds.

Published
2009
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17. Synthesis of 9-oxime-11,12-carbamate ketolides Through a novel N-deamination reaction of 11,12-hydrazonocarbamate ketolide

Author

Jean-Marie Pejac, Alexis Denis, Francois Bretin, and Alain Bonnefoy

Subjects
Carbamate, Streptococcus pyogenes, Stereochemistry, medicine.medical_treatment, Clinical Biochemistry, Molecular Conformation, Deamination, Pharmaceutical Science, Microbial Sensitivity Tests, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Oximes, Drug Discovery, medicine, Molecular Biology, Ketolide, Bond cleavage, Antibacterial agent, Organic Chemistry, Oxime, Anti-Bacterial Agents, Streptococcus pneumoniae, chemistry, Reagent, Molecular Medicine, Carbamates, Macrolides, medicine.drug
Abstract

A series of 9-oxime-11,12-carbamate ketolides was synthesized for the first time through a key 11,12-hydrazonocarbamate intermediate that was first oximated and further deaminated to give the corresponding carbamate. The N-N bond cleavage was achieved through an original new reaction using glycoaldehyde dimer as deaminating reagent. The new compounds synthesized were shown to display improved antibacterial activities against Streptococcus pneumoniae and S. pyogenes resistant to erythromycin.

Published
2003
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18. β-Keto-ester chemistry and ketolides. synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides

Author

Alexis Denis, A Bonnet, Alain Bonnefoy, Claude Fromentin, G Piltan, Constantin Agouridas, and Francois Bretin

Subjects
Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Mice, Structure-Activity Relationship, In vivo, Drug Discovery, medicine, Animals, Structure–activity relationship, Molecular Biology, Ketolide, Antibacterial agent, chemistry.chemical_classification, Bacteria, Organic Chemistry, Aminoglycoside, Bacterial Infections, Anti-Bacterial Agents, chemistry, Enol ether, Molecular Medicine, Macrolides, Antibacterial activity, Lactone, medicine.drug
Abstract

The effect of 2,3 modifications on the antibacterial activity of ketolides was evaluated by introducing substituents in position 2 and converting the C-1, C-2, C-3 beta-keto-ester into stable 2,3 enol-ether or 2,3 anhydro derivatives. Introduction of a fluorine in C-2 is beneficial with regard to the overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturated compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluoro ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae. Compared to azithromycin against Haemophilus influenzae, this compound is equivalent in vitro and slightly more active in vivo. These results demonstrate that within the ketolide class, to retain good antibacterial activity, position 2 needs to remain tetrahedral and tolerates only very small substituents such as fluorine.

Published
2000
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19. Novel HldE-K inhibitors leading to attenuated Gram negative bacterial virulence

Author

Nicolas Desroy, Vanida Vongsouthi, Stéphanie Floquet, Dmytro Atamanyuk, Vincent Gerusz, Géraldine LeFralliec, François Moreau, Theodore B. Verhey, Ting-Wai Lee, Lionel Durant, Yannick Bonvin, Sophia Briet, Alexis Denis, Mayalen Oxoby, Fabien Faivre, Elodie Drocourt, Sonia Escaich, Chrystelle Oliveira, and Murray S. Junop

Subjects
Lipopolysaccharides, Gram-negative bacteria, medicine.drug_class, Antibiotics, Virulence, Microbial Sensitivity Tests, Bacterial growth, Microbiology, Structure-Activity Relationship, Multienzyme Complexes, Drug Discovery, medicine, Escherichia coli, Benzothiazoles, Pathogen, biology, Kinase, Chemistry, Triazines, biology.organism_classification, Nucleotidyltransferases, Anti-Bacterial Agents, Phosphotransferases (Alcohol Group Acceptor), Molecular Medicine, Efflux, Bacteria
Abstract

We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.

Published
2013

22. Structure-activity relationship analysis of the peptide deformylase inhibitor 5-bromo-1H-indole-3-acetohydroxamic acid

Author

Frédéric Dardel, Valéry Larue, Thierry Meinnel, Coralie Soulama, Carmela Giglione, Isabelle Artaud, Yann Duroc, Alexis Denis, Sylvain Petit, Carole Léon, Laboratoire Léon Brillouin (LLB - UMR 12), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), CNRS Region Ile-de-France Agence Nationale de la Recherche (ANR, France) ANR-06-MIME-010, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire Léon Brillouin ( LLB - UMR 12 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut Jean-Pierre Bourgin ( IJPB ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des sciences du végétal ( ISV ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, MESH: Amidohydrolases, MESH: Hydroxamic Acids, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, Magnetic Resonance Spectroscopy, Peptide, Hydroxamic Acids, 01 natural sciences, Biochemistry, antibiotics, chemistry.chemical_compound, Peptide deformylase, MESH: Structure-Activity Relationship, MESH : Indoles, Drug Discovery, MESH : Structure-Activity Relationship, inhibitors, Enzyme Inhibitors, General Pharmacology, Toxicology and Pharmaceutics, MESH : Anti-Bacterial Agents, Actinonin, chemistry.chemical_classification, MESH: Indoles, 0303 health sciences, peptide deformylase, MESH: Microbial Sensitivity Tests, Chemistry, MESH : Spectrometry, Mass, Electrospray Ionization, Anti-Bacterial Agents, MESH : Amidohydrolases, MESH: Enzyme Inhibitors, Molecular Medicine, Antibacterial activity, Lead compound, MESH: Models, Molecular, Spectrometry, Mass, Electrospray Ionization, Stereochemistry, MESH : Models, Molecular, Microbial Sensitivity Tests, MESH: Spectrometry, Mass, Electrospray Ionization, Amidohydrolases, Structure-Activity Relationship, 03 medical and health sciences, NMR spectroscopy, MESH: Anti-Bacterial Agents, Structure–activity relationship, Potency, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, 030304 developmental biology, Pharmacology, Indole test, MESH : Enzyme Inhibitors, MESH : Hydroxamic Acids, 010405 organic chemistry, MESH: Magnetic Resonance Spectroscopy, Organic Chemistry, indoles, 0104 chemical sciences, MESH : Magnetic Resonance Spectroscopy, MESH : Microbial Sensitivity Tests
Abstract

International audience; The lead compound 5-bromoindolyl-3-acetohydroxamic acid (10) was recently identified as a potent inhibitor of bacterial peptide deformylases (PDFs). The synthesis and associated activities of new variants were investigated at position 5 to optimize the fit at the S1' subsite and at position 1 to improve both potency and antibacterial activity. A morphomimetic series, termed "reverse-indole" was synthesized. The indole derivatives remain selective in vitro inhibitors of PDF2 over PDF1. Bromide is the best group at position 5 and cannot be replaced by bulkier substituents. In this series, an N-benzyl group at position 1 in 19 e improves the potency relative to 10. In the case of PDF1, and unlike PDF2, potency is increased as the alkyl chain becomes longer and more ramified. These data support the results of NMR footprinting experiments that were performed with (15)N-labeled Ni-PDF and the corresponding 3-acetic acid derivatives. Most of the compounds have antibacterial activities toward B. subtilis, but are inefficient toward E. coli owing to active removal by the major efflux pumps. Among the reverse-indole derivatives, 23 c, which is the exact mirror image of 19 e, shows strong potency in vitro against PDF2, but little against PDF1, although this compound displays significant antibacterial activity toward an efflux-minus mutant of E. coli. All the compounds were assessed with major pathogenic bacteria, but most of them are inefficient antibacterial agents. The reverse-indole compounds 23 a and 23 c have potency against S. pneumoniae that is similar to that of actinonin.

Published
2009
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23. Discovery of new Gram-negative antivirulence drugs: structure and properties of novel E. coli WaaC inhibitors

Author

Jean-Marie Genevard, Vanida Vongsouthi, M. Busemann, K. Wolf, G. Le Fralliec, A. Aschenbrenner, Alexis Denis, Vincent Gerusz, Chrystelle Oliveira, Sonia Escaich, Nicolas Desroy, Stéphanie Floquet, and François Moreau

Subjects
Heptosyltransferase, Antivirulence, Chemistry, Pharmaceutical, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Microbial Sensitivity Tests, Crystallography, X-Ray, Biochemistry, Models, Biological, Structure-Activity Relationship, Anti-Infective Agents, Drug Resistance, Multiple, Bacterial, Drug Discovery, Anti infectives, Molecular Biology, Virtual screening, Binding Sites, Molecular Structure, Chemistry, Organic Chemistry, Glycosyltransferases, Anti-Bacterial Agents, Kinetics, Models, Chemical, Drug Design, Molecular Medicine
Abstract

Heptosyltransferases such as WaaC represent promising and attractive targets for the discovery of new Gram-negative antibacterial drugs based on antivirulence mechanisms. We report herein our approach to the identification of the first micromolar inhibitors of WaaC and the preliminary SAR generated from this family of 2-aryl-5-methyl-4-(5-aryl-furan-2-yl-methylene)-2,4-dihydro-pyrazol-3-ones identified by virtual screening.

Published
2008

24. Molecular genetic studies on the thiol-disulfide oxidoreductase lipoprotein DsbA and the alternative sigma factor SigH of Staphylococcus aureus

Author

Dumoulin, Alexis Denis

Subjects
TRANSKRIPTIONSREGULATION (MOLEKULARE GENETIK), OXIDOREDUCTASES, DEHYDROGENASES,OXIDASES, REDUCTASES (ENZYMES), MICROBIAL PATHOGENICITY + MICROBIAL VIRULENCE (MICROBIOLOGY), STAPHYLOCOCCUS AUREUS (MIKROBIOLOGIE), BIOCHEMISCHE UND MOLEKULARBIOLOGISCHE EXPERIMENTE, METHODEN UND TECHNIKEN, TRANSCRIPTIONAL REGULATION (MOLECULAR GENETICS), PATHOGENITÄT VON MIKROORGANISMEN + VIRULENZ VON MIKROORGANISMEN (MIKROBIOLOGIE), Life sciences, ANALYTISCHE ENZYMOLOGIE + ENZYMANALYSE (BIOLOGISCHE TECHNIKEN), OXYDOREDUKTASEN, DEHYDROGENASEN, REDUKTASEN (ENZYME), STAPHYLOCOCCUS AUREUS (MICROBIOLOGY), ANALYTICAL ENZYMOLOGY + ENZYME ANALYSIS (BIOLOGICAL TECHNIQUES), BIOCHEMICAL AND MOLECULAR BIOLOGICAL EXPERIMENTS, METHODS AND TECHNIQUES
Published
2005
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25. Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors

Author

Alexis Denis, Philippe Cluzeau, Pierre Ducrot, Renaud Morales, Anne-Claude Dublanchet, Anita Tertre, Delphine Compere, Marie-Laure Prunet, Jacques Hamon, Stéphane Blais, Margaret O'Gara, Charles Andrianjara, Karine Courte, and François Moreau

Subjects
Models, Molecular, Molecular model, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, chemistry.chemical_element, Zinc, Matrix metalloproteinase, Crystallography, X-Ray, Biochemistry, Chemical synthesis, Structure-Activity Relationship, Matrix Metalloproteinase 12, Drug Discovery, Humans, Chelation, Enzyme Inhibitors, Molecular Biology, Chelating Agents, chemistry.chemical_classification, Binding Sites, biology, Molecular Structure, Organic Chemistry, Active site, Metalloendopeptidases, Enzyme, chemistry, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine
Abstract

A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.

Published
2004

26. Ketolides: novel antibacterial agents designed to overcome resistance to erythromycin A within gram-positive cocci

Author

Alexis Denis and André Bryskier

Subjects
Drug, biology, business.industry, media_common.quotation_subject, Erythromycin, medicine.disease_cause, biology.organism_classification, Microbiology, Penicillin, Moraxella catarrhalis, Pharmacokinetics, Staphylococcus aureus, medicine, Gram-Positive Cocci, business, medicine.drug, media_common, Antibacterial agent
Abstract

Erythromycin A [1] was discovered at a time when a new drug active against penicillinase-producing Staphylococcus aureus strains was needed. Penicillinaseproducing resistant strains appeared in London hospitals very shortly after the early clinical use of penicillin G, and they soon spread worldwide [2]. Erythromycin use rapidly was limited by the development of other drugs active on penicillin G-resistant S. aureus isolates and by the fact that it shows only a bacteriostatic activity. In addition, erythromycin’ s pharmacokinetic behaviour is erratic, as the compound is unstable in acidic condition [3].

Published
2002
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27. Cover Picture: Structure-Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5-Bromo-1H-indole-3-acetohydroxamic Acid (ChemMedChem 2/2009)

Author

Isabelle Artaud, Carmela Giglione, Frédéric Dardel, Alexis Denis, Yann Duroc, Carole Léon, Coralie Soulama, Sylvain Petit, Valéry Larue, and Thierry Meinnel

Subjects
Pharmacology, Chemistry, Stereochemistry, Organic Chemistry, Nuclear magnetic resonance spectroscopy, Biochemistry, Combinatorial chemistry, Peptide deformylase, 5-bromo-1H-indole-3-acetohydroxamic acid, Drug Discovery, Molecular Medicine, Structure–activity relationship, Cover (algebra), General Pharmacology, Toxicology and Pharmaceutics
Published
2009
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