Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function

Amin Sagar, Ehtesham Arif, Ashish Kumar Solanki, Pankaj Srivastava, Michael G. Janech, Seok Hyung Kim, Joshua H. Lipschutz, Sang Ho Kwon, Ashish, Deepak Nihalani

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Article number12047
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function'. Together they form a unique fingerprint.

  • Cite this

    Sagar, A., Arif, E., Solanki, A. K., Srivastava, P., Janech, M. G., Kim, S. H., Lipschutz, J. H., Kwon, S. H., Ashish, & Nihalani, D. (2017). Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function. Scientific reports, 7(1), [12047]. https://doi.org/10.1038/s41598-017-12134-8