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5 results on '"Léo Faïon"'

1. Rapid and Efficient Access to Novel Bio-Inspired 3-Dimensional Tricyclic SpiroLactams as Privileged Structures via Meyers’ Lactamization

Author

Salia Tangara, Léo Faïon, Catherine Piveteau, Frédéric Capet, Romain Godelier, Marion Michel, Marion Flipo, Benoit Deprez, Nicolas Willand, and Baptiste Villemagne

Subjects
focused chemical library, natural-like products, tricyclic spirolactams, Fsp3-rich compounds, privileged scaffolds, Medicine, Pharmacy and materia medica, RS1-441
Abstract

The concept of privileged structure has been used as a fruitful approach for the discovery of novel biologically active molecules. A privileged structure is defined as a semi-rigid scaffold able to display substituents in multiple spatial directions and capable of providing potent and selective ligands for different biological targets through the modification of those substituents. On average, these backbones tend to exhibit improved drug-like properties and therefore represent attractive starting points for hit-to-lead optimization programs. This article promotes the rapid, reliable, and efficient synthesis of novel, highly 3-dimensional, and easily functionalized bio-inspired tricyclic spirolactams, as well as an analysis of their drug-like properties.

Published
2023
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2. Exploring the Antitubercular Activity of Anthranilic Acid Derivatives: From MabA (FabG1) Inhibition to Intrabacterial Acidification

Author

Léo Faïon, Kamel Djaout, Catalin Pintiala, Catherine Piveteau, Florence Leroux, Alexandre Biela, Stéphanie Slupek, Rudy Antoine, Monika Záhorszká, Francois-Xavier Cantrelle, Xavier Hanoulle, Jana Korduláková, Benoit Deprez, Nicolas Willand, Alain R. Baulard, and Marion Flipo

Subjects
MabA inhibitors, anthranilic acid, FabG1, tuberculosis, mycolic acids, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, is responsible for the death of 1.5 million people each year and the number of bacteria resistant to the standard regimen is constantly increasing. This highlights the need to discover molecules that act on new M. tuberculosis targets. Mycolic acids, which are very long-chain fatty acids essential for M. tuberculosis viability, are synthesized by two types of fatty acid synthase (FAS) systems. MabA (FabG1) is an essential enzyme belonging to the FAS-II cycle. We have recently reported the discovery of anthranilic acids as MabA inhibitors. Here, the structure–activity relationships around the anthranilic acid core, the binding of a fluorinated analog to MabA by NMR experiments, the physico-chemical properties and the antimycobacterial activity of these inhibitors were explored. Further investigation of the mechanism of action in bacterio showed that these compounds affect other targets than MabA in mycobacterial cells and that their antituberculous activity is due to the carboxylic acid moiety which induces intrabacterial acidification.

Published
2023
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3. On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9–10 December 2021

Author

Kevin Antraygues, Nina Compagne, Francesca Ruggieri, Kamel Djaout, Zainab Edoo, Maxime Eveque, Léo Faïon, Bruna Gioia, Salia Tangara, Anais Vieira Da Cruz, Baptiste Villemagne, Marion Flipo, Alain Baulard, and Nicolas Willand

Subjects
antimicrobial resistance, drug discovery, microbiology, Medicine, Pharmacy and materia medica, RS1-441
Abstract

The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Société de chimie thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) to organize their joint autumn symposium (entitled “On the hunt for next-generation antimicrobial agents”) online on 9–10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event.

Published
2022
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4. Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases

Author

Sushovan Dam, Salia Tangara, Claire Hamela, Theo Hattabi, Léo Faïon, Paul Carre, Rudy Antoine, Adrien Herledan, Florence Leroux, Catherine Piveteau, Maxime Eveque, Marion Flipo, Benoit Deprez, Laurent Kremer, Nicolas Willand, Baptiste Villemagne, Ruben C. Hartkoorn, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), the CPER grants were funded by European Union under the European Regional Development Fund (ERDF) and by the Hauts de Franceregional Council (contract n°20002842 and contract n°18006176), ANR-16-IDEX-0004,ULNE,ULNE(2016), ANR-19-CE18-0034,NL4TB,Nouvelle génération de composés Lead pour combattre la tuberculose(2019), and Willand, Nicolas

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Antitubercular Agents, Mycobacterium tuberculosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [CHIM.ORGA] Chemical Sciences/Organic chemistry, NAD, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Drug Discovery, Animals, Molecular Medicine, NADH, NADPH Oxidoreductases, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Zebrafish
Abstract

International audience; It is critical that novel classes of antituberculosis drugs are developed to combat the increasing burden of infections by multidrug-resistant strains. To identify such a novel class of antibiotics, a chemical library of unique 3-D bioinspired molecules was explored revealing a promising, mycobacterium specific Tricyclic SpiroLactam (TriSLa) hit. Chemical optimization of the TriSLa scaffold delivered potent analogues with nanomolar activity against replicating and nonreplicating Mycobacterium tuberculosis. Characterization of isolated TriSLa-resistant mutants, and biochemical studies, found TriSLas to act as allosteric inhibitors of type II NADH dehydrogenases (Ndh-2 of the electron transport chain), resulting in an increase in bacterial NADH/NAD+ ratios and decreased ATP levels. TriSLas are chemically distinct from other inhibitors of Ndh-2 but share a dependence for fatty acids for activity. Finally, in vivo proof-of-concept studies showed TriSLas to protect zebrafish larvae from Mycobacterium marinum infection, suggesting a vulnerability of Ndh-2 inhibition in mycobacterial infections.

Published
2022

5. Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening

Author

Martin Moune, Florence Leroux, Léo Faïon, Abdalkarim Tanina, Alexandre Biela, Nicolas Willand, Kevin Bourbiaux, Francois-Xavier Cantrelle, Alain R. Baulard, Laurent Kremer, Catalin Pintiala, Benoit Deprez, Kamel Djaout, René Wintjens, Adrien Herledan, Marion Flipo, Mickaël Blaise, Rosangela Frita, Alexandre Vandeputte, Catherine Piveteau, Xavier Hanoulle, Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Biologie Structurale Intégrative (ERL 9002 - BSI ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité Microbiologie, Chimie Bioorganique et Macromoléculaire (CP206/04), Département RD3, ANR-13-JSV5-0010,2FightTb,De l'identification de fragments à la découverte d'inhibiteurs de MabA (FabG1) un nouveau challenge pour traiter la tuberculose(2013), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), HANOULLE, Xavier, and Jeunes Chercheuses et Jeunes Chercheurs - De l'identification de fragments à la découverte d'inhibiteurs de MabA (FabG1) un nouveau challenge pour traiter la tuberculose - - 2FightTb2013 - ANR-13-JSV5-0010 - JC - VALID

Subjects
Drug Evaluation, Preclinical, 01 natural sciences, Mycolic acid, chemistry.chemical_compound, [CHIM] Chemical Sciences, mycolic acid, Drug Discovery, Fragment, ortho-Aminobenzoates, Enzyme Inhibitors, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], chemistry.chemical_classification, 0303 health sciences, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, INHA, General Medicine, Sciences bio-médicales et agricoles, 3. Good health, Fatty acid synthase, Biochemistry, tuberculosis, Tuberculosis, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], fragment, Mycobacterium tuberculosis, 03 medical and health sciences, Structure-Activity Relationship, Biosynthesis, Bacterial Proteins, Anthranilic acid, medicine, MabA inhibitors, [CHIM]Chemical Sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Pharmacology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, medicine.disease, biology.organism_classification, 0104 chemical sciences, Enzyme, chemistry, biology.protein, Fatty Acid Synthases, FabG1
Abstract

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments., info:eu-repo/semantics/published

Published
2020

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