2. Academic Validation
  3. Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening

Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening

  • Sci Rep. 2017 Jun 13;7(1):3424. doi: 10.1038/s41598-017-03427-z.
Hadley Mouhsine 1 2,  Hélène Guillemain 1 2,  Gabriel Moreau 1 2,  Najla Fourati 3,  Chouki Zerrouki 3,  Bruno Baron 4,  Lucille Desallais 1 2,  Patrick Gizzi 5,  Nesrine Ben Nasr 1,  Julie Perrier 1,  Rojo Ratsimandresy 1,  Jean-Louis Spadoni 1,  Hervé Do 1 2,  Patrick England 4,  Matthieu Montes 6,  Jean-François Zagury 7
Affiliations

Affiliations

  • 1 Laboratoire Génomique, Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, France.
  • 2 Peptinov SAS, Pépinière Cochin Santé, Hôpital Cochin, 29 rue du Faubourg Saint Jacques, 75014, Paris, France.
  • 3 Laboratoire SATIE, CNRS, UMR 8029, Conservatoire National des Arts et Métiers, 292 rue Saint Martin, 75003, Paris, France.
  • 4 Plate-forme de Biophysique des Macromolécules et de leurs Interactions, Proteopole Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France.
  • 5 CNRS, UMR 7242, TechMedill, Bd Sebastien Brant, 67121, Illkirch, France.
  • 6 Laboratoire Génomique, Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, France. [email protected].
  • 7 Laboratoire Génomique, Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003, Paris, France. [email protected].
PMID: 28611375 DOI: 10.1038/s41598-017-03427-z
Abstract

TNFα is a homotrimeric pro-inflammatory cytokine, whose direct targeting by protein biotherapies has been an undeniable success for the treatment of chronic inflammatory diseases. Despite many efforts, no orally active drug targeting TNFα has been identified so far. In the present work, we identified through combined in silico/in vitro/in vivo approaches a TNFα direct inhibitor, compound 1, displaying nanomolar and micromolar range bindings to TNFα. Compound 1 inhibits the binding of TNFα with both its receptors TNFRI and TNFRII. Compound 1 inhibits the TNFα induced Apoptosis on L929 cells and the TNFα induced NF-κB activation in HEK cells. In vivo, oral administration of compound 1 displays a significant protection in a murine TNFα-dependent hepatic shock model. This work illustrates the ability of low-cost combined in silico/in vitro/in vivo screening approaches to identify orally available small-molecules targeting challenging protein-protein interactions such as homotrimeric TNFα.

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