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.
Highlights
Protein complexes actively participate in many biological processes and disease pathologies making them an attractive target for drug developers[1,2]
Targeting protein-protein interaction (PPI) is a fast developing approach that has led to the identifications of many small molecules with potential to treat a variety of cancers[1,2,4]
In addition to its interaction with ZO-1, Neph[1] interaction with Nephrin may be critical for podocyte function[15,19], as it has been shown to play a key role in maintaining podocyte integrity
Summary
Protein complexes actively participate in many biological processes and disease pathologies making them an attractive target for drug developers[1,2]. Injury to glomerulus has been shown to dissociate Neph1-Nephrin and Neph1-ZO-1 complexes and induce redistribution of these proteins from podocyte cell membrane to cytoplasm[10,23,24] These proteins and their complexes may define the structural integrity of slit diaphragm, which is prone to damage during glomerular injury. We published the structural details of this interaction which provided novel insights into the nature of this complex Based on these facts we hypothesized that the Neph[1] interactions at podocyte cell membrane are critical for maintaining the structural integrity of podocytes and regulate podocyte function[11]. The results presented in this study show the applicability of this novel approach in identifying potential molecules such as ISD that may have the ability to enhance Neph[1] and ZO-1 interaction (or interactions of other podocyte proteins), which may contribute towards protection of podocytes from injury
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