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

ABSTRACT: TNF? 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 TNF? has been identified so far. In the present work, we identified through combined in silico/in vitro/in vivo approaches a TNF? direct inhibitor, compound 1, displaying nanomolar and micromolar range bindings to TNF?. Compound 1 inhibits the binding of TNF? with both its receptors TNFRI and TNFRII. Compound 1 inhibits the TNF? induced apoptosis on L929 cells and the TNF? induced NF-?B activation in HEK cells. In vivo, oral administration of compound 1 displays a significant protection in a murine TNF?-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 TNF?.

SUBMITTER: Mouhsine H 

PROVIDER: S-EPMC5469758 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature