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

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.
Type de document :
Article dans une revue
Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.3424. 〈10.1038/s41598-017-03427-z〉
Liste complète des métadonnées

Littérature citée [39 références]  Voir  Masquer  Télécharger

https://hal.archives-ouvertes.fr/hal-01679350
Contributeur : Chouki Zerrouki <>
Soumis le : mardi 9 janvier 2018 - 19:20:53
Dernière modification le : jeudi 18 octobre 2018 - 17:31:10
Document(s) archivé(s) le : jeudi 3 mai 2018 - 16:58:41

Fichier

Identification of an in vivo o...
Publication financée par une institution

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Citation

Hadley Mouhsine, Hélène Guillemain, Gabriel Moreau, Najla Fourati, Chouki Zerrouki, et al.. Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening. Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.3424. 〈10.1038/s41598-017-03427-z〉. 〈hal-01679350〉

Partager

Métriques

Consultations de la notice

160

Téléchargements de fichiers

160