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Proc Natl Acad Sci U S A ; 121(5): e2308776121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38252831


We present a drug design strategy based on structural knowledge of protein-protein interfaces selected through virus-host coevolution and translated into highly potential small molecules. This approach is grounded on Vinland, the most comprehensive atlas of virus-human protein-protein interactions with annotation of interacting domains. From this inspiration, we identified small viral protein domains responsible for interaction with human proteins. These peptides form a library of new chemical entities used to screen for replication modulators of several pathogens. As a proof of concept, a peptide from a KSHV protein, identified as an inhibitor of influenza virus replication, was translated into a small molecule series with low nanomolar antiviral activity. By targeting the NEET proteins, these molecules turn out to be of therapeutic interest in a nonalcoholic steatohepatitis mouse model with kidney lesions. This study provides a biomimetic framework to design original chemistries targeting cellular proteins, with indications going far beyond infectious diseases.

Influenza Humana , Vírus , Animais , Camundongos , Humanos , Proteoma , Peptídeos/farmacologia , Descoberta de Drogas
J Med Chem ; 61(6): 2246-2265, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29446942


Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.

Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Fibrose/prevenção & controle , Indóis/síntese química , Indóis/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Benzotiazóis/farmacocinética , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Linhagem Celular , Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
FASEB J ; 24(5): 1506-17, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20040517


Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, nonpeptidic agonists and antagonists of the apelin receptor are required. To identify such compounds that do not exist to date, we used an original fluorescence resonance energy transfer-based assay to screen a G-protein-coupled receptor-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolated E339-3D6 that displayed a 90 nM affinity and behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first nonpeptidic agonist of the apelin receptor, the optimization of which will allow development of a new generation of vasodilator and aquaretic agents.

Dipeptídeos/farmacologia , Fluoresceínas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Aorta/efeitos dos fármacos , Receptores de Apelina , Colforsina/farmacologia , AMP Cíclico/metabolismo , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos/métodos , Fluoresceínas/química , Fluoresceínas/isolamento & purificação , Transferência Ressonante de Energia de Fluorescência/métodos , Humanos , Masculino , Camundongos , Ratos , Ratos Endogâmicos WKY , Vasodilatação , Vasopressinas/metabolismo
J Med Chem ; 48(24): 7847-59, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16302823


The efficiency of fluorescence resonance energy transfer (FRET) is dependent upon donor-acceptor proximity and spectral overlap, whether the acceptor partner is fluorescent or not. We report here on the design, synthesis, and characterization of two novel pirenzepine derivatives that were coupled to patent blue VF and pinacyanol dyes. These nonfluorescent compounds, when added to cells stably expressing enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors, promote EGFP fluorescence extinction in a time-, concentration-, and atropine-dependent manner. They display nanomolar affinity for the muscarinic receptor, determined using either FRET or classical radioligand binding conditions. We provide evidence that these compounds behave as potent acceptors of energy from excited EGFP with quenching efficiencies comparable to those of analogous fluorescent bodipy or rhodamine red pirenzepine derivatives. The advantages they offer over fluorescent ligands are illustrated and discussed in terms of reliability, sensitivity, and wider applicability of FRET-based receptor binding assays.

Benzenossulfonatos/síntese química , Benzodiazepinonas/síntese química , Corantes/síntese química , Proteínas de Fluorescência Verde/metabolismo , Pirenzepina/análogos & derivados , Pirenzepina/síntese química , Compostos de Quinolínio/síntese química , Receptor Muscarínico M1/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Benzenossulfonatos/química , Benzodiazepinonas/química , Compostos de Boro , Linhagem Celular , Corantes/química , Transferência Ressonante de Energia de Fluorescência , Proteínas de Fluorescência Verde/genética , Humanos , Ligantes , Pirenzepina/química , Compostos de Quinolínio/química , Ensaio Radioligante , Receptor Muscarínico M1/genética , Proteínas Recombinantes de Fusão/genética
J Med Chem ; 47(17): 4300-15, 2004 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-15294002


Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.

Corantes Fluorescentes/síntese química , Pirenzepina/análogos & derivados , Pirenzepina/síntese química , Receptor Muscarínico M1/efeitos dos fármacos , Estricnina/análogos & derivados , Regulação Alostérica , Sítios de Ligação , Ligação Competitiva , Compostos de Boro/química , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/farmacologia , Proteínas de Fluorescência Verde , Humanos , Cinética , Ligantes , Proteínas Luminescentes/genética , Pirenzepina/farmacologia , Ensaio Radioligante , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Rodaminas/química , Relação Estrutura-Atividade , Estricnina/farmacologia