40 research outputs found
Virtual screening for inhibitors of the human TSLP:TSLPR interaction
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation
Mortality in premature mice at birth and during neonatal development
International audienc
Sécrétion, métabolisme et transport de l'aldostérone dans la période néonatale chez le Cobaye
International audienc
Maturation of glucocorticosteroid activity in the foetal guinea-pig during the end of gestation
International audienc
The regulation of glucocorticosteroid secretion during the perinatal period
International audienc
Liaison spécifique du cortisol aux protéines plasmatiques chez le Cobaye, de la naissance au sevrage
International audienc
Sodium and potassium in blood and milk and plasma aldosterone levels in high-yield dairy cows
International audienc