Investigating the specificity of endothelin-traps as a potential therapeutic tool for endothelin-1 related disorders

doi:10.4239/wjd.v13.i6.434

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World Journal of Diabetes

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World J Diabetes. Jun 15, 2022; 13(6): 434-441
Published online Jun 15, 2022. doi: 10.4239/wjd.v13.i6.434

Investigating the specificity of endothelin-traps as a potential therapeutic tool for endothelin-1 related disorders

Arjun Jain, Kristof Bozovicar, Vidhi Mehrotra, Tomaz Bratkovic, Martin H Johnson, Ira Jha

Arjun Jain, Vidhi Mehrotra, Ira Jha, ET-Traps Limited, Cambridge CB3 0JE, United Kingdom

Arjun Jain, Martin H Johnson, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom

Arjun Jain, Vidhi Mehrotra, Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom

Kristof Bozovicar, Tomaz Bratkovic, Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Slovenia 1000, Slovenia

Author contributions: Jain A and Bozovičar K contributed equally to this work; Jain A, Bozovičar K, Mehrotra V, Bratkovič T performed the experimental analyses and contributed towards writing the article and Johnson M and Jha I revised it critically for important intellectual content.

Institutional review board statement: This study was approved by ET-traps Limited.

Conflict-of-interest statement: The authors have no conflict of interest.

Data sharing statement: Data available from corresponding author, Dr. Arjun Jain at arjun@et-traps.co.uk.

Corresponding author: Arjun Jain, MPhil, PhD, Research Scientist, ET-Traps Limited, 28 St Stephens Place, Cambridge CB3 0JE, United Kingdom. jain_arjun@yahoo.com

Received: January 27, 2022
Peer-review started: January 27, 2022
First decision: April 18, 2022
Revised: April 24, 2022
Accepted: May 28, 2022
Article in press: May 28, 2022
Published online: June 15, 2022
Processing time: 131 Days and 5.6 Hours

Abstract

BACKGROUND

Endothelin (ET)-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. Previous work has shown that use of the selected ET-traps potently and significantly reduces different markers of diabetes pathology back to normal, non-disease levels.

AIM

To demonstrate the selected ET-traps potently and significantly bind to ET-1.

METHODS

We performed phage display experiments to test different constructs of ET-traps, and conducted bio-layer interferometry binding assays to verify that the selected ET-traps bind specifically to ET-1 and display binding affinity in the double-digit picomolar range (an average of 73.8 rM, n = 6).

RESULTS

These experiments have confirmed our choice of the final ET-traps and provided proof-of-concept for the potential use of constructs as effective biologics for diseases associated with pathologically elevated ET-1.

CONCLUSION

There is increased need for such therapeutics as they could help save millions of lives around the world.

Keywords: Endothelin-1; Endothelin-traps; Diabetes; Heart failure; Chronic kidney disease; Novel therapeutic

Core Tip: This study verified the specificity of endothelin (ET)-traps, which are an Fc-based fusion protein that acts as a potential therapeutic for various cET-1 related disorders, including diabetes and chronic kidney disease. ET-traps, unlike ET receptor antagonists, do not completely block the ET system and hence have minimal side effects. ET-traps would help save millions of lives around the world.