Since its discovery in 1989, there has been extensive research on endothelin (ET)-1 physiology, as well as pathology. Accordingly, there is considerable research on the discovery of therapeutics based around ET-1, amongst which current treatment options include endothelin receptor antagonists. These target the ET-1 receptors, which are G-protein–coupled receptors (GPCRs). We have effectively developed a soluble form of a GPCR that binds to ligands, by constructing a fusion polypeptide of different endothelin receptor ligand binding domains. Phage experiments identified strong binders to ET-1. We then constructed Fc-fusions of the top binders and further binding assays revealed a KD of 21.2 nM for the Fc-ETtr1 construct and KD of 77.3 nM for the Fc-ETtr2 construct. These constructs are soluble and have the ability to bind and potentially sequester elevated ET-1 levels that are prevalent in different diseases. These results provide a novel approach to targeting GPCR–binding ligands, and thereby to contribute to a very important class of therapeutics.
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We would like to thank DM; Ms. Leela Jain for all her support. We also thank RC for funding this project.
This project was funded by private funding.
Conflict of interest
The author(s) declare that they have no competing interests.
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Jain, A., Mehrotra, V., Yong, H. et al. Creating a Soluble Binder to Endothelin-1 Based on the Natural Ligand Binding Domains of the Endothelin-1 (G-Protein-Coupled) Receptor. Int J Pept Res Ther 25, 107–114 (2019). https://doi.org/10.1007/s10989-017-9653-x
- ETA receptor
- ETB receptor
- Endothelin-1 traps
- FFP (Fc-fusion proteins)
- GPCR (G-protein-coupled receptors)