creators_name: Sagar, Amin
creators_name: Arif, Ehtesham
creators_name: Solanki, Ashish Kumar
creators_name: Srivastava, Pankaj
creators_name: Janech, Michael G.
creators_name: Kim, Seok-Hyung
creators_name: Lipschutz, Joshua H.
creators_name: Kwon, Sang-Ho
creators_name: Ashish, .
creators_name: Nihalani, Deepak
type: article
datestamp: 2018-03-28 05:42:33
lastmod: 2018-10-31 06:32:51
metadata_visibility: show
title: Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function
ispublished: pub
subjects: QR
note: Open Access 
abstract: Targeting protein-protein interaction (PPI) is rapidly becoming an attractive alternative for drug development. While drug development commonly involves inhibiting a PPI, in this study, we show that stabilizing PPI may also be therapeutically beneficial. Junctional proteins Neph1 and ZO-1 and their interaction is an important determinant of the structural integrity of slit diaphragm, which is a critical component of kidney's filtration system. Since injury induces loss of this interaction, we hypothesized that strengthening this interaction may protect kidney's filtration barrier and preserve kidney function. In this study, Neph1-ZO-1 structural complex was screened for the presence of small druggable pockets formed from contributions from both proteins. One such pocket was identified and screened using a small molecule library. Isodesmosine (ISD) a rare naturally occurring amino acid and a biomarker for pulmonary arterial hypertension was selected as the best candidate and to establish the proof of concept, its ability to enhance Neph1-CD and ZO-1 binding was tested. Results from biochemical binding analysis showed that ISD enhanced Neph1 and ZO-1 interaction under in vitro and in vivo conditions. Importantly, ISD treated podocytes were resistant to injury-induced loss of transepithelial permeability. Finally, mouse and zebrafish studies show that ISD protects from injury-induced renal damage.
date: 2017
date_type: published
publication: Scientific Reports
volume: 7
publisher: Nature Publishing Group
id_number: doi:10.1038/s41598-017-12134-8
refereed: TRUE
issn: 2045-2322
official_url: http://dx.doi.org/10.1038/s41598-017-12134-8
citation:   Sagar, Amin and Arif, Ehtesham and Solanki, Ashish Kumar and Srivastava, Pankaj and Janech, Michael G. and Kim, Seok-Hyung and Lipschutz, Joshua H. and Kwon, Sang-Ho and Ashish, . and Nihalani, Deepak  (2017) Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function.  Scientific Reports, 7.   ISSN 2045-2322