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Published on: February 15, 2018
The ring size of monocyclic ET-1 controls selectivity and signaling efficiency at both endothelin receptor subtypes
Philipp Wolf1, Annette G Beck-Sickinger1
1Faculty of Life Sciences, Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Insights
Researchers developed novel endothelin-1 (ET-1) analogs to target cardiovascular diseases (CVDs). Modifying peptide ring size enhanced selectivity for endothelin B receptor (ETB R) over endothelin A receptor (ETA R), aiding drug development.
Area of Science:
- Pharmacology and Medicinal Chemistry
- Cardiovascular Research
- Molecular Biology
Background:
- Cardiovascular diseases (CVDs), including hypertension, are leading global causes of mortality.
- The endothelin system, comprising endothelin-1 (ET-1) and its receptors (ETA R and ETB R), critically regulates vascular tone and blood pressure.
- Dysregulation of the endothelin system contributes to severe CVDs like pulmonary artery hypertension, necessitating targeted therapeutic strategies.
Purpose of the Study:
- To design and pharmacologically characterize novel endothelin-1 (ET-1) analogs with improved selectivity for ETA R and ETB R.
- To investigate the impact of structural modifications, specifically intramolecular ring size, on receptor-ligand interactions and signaling.
- To identify potential therapeutic leads for cardiovascular diseases by understanding ET-1/receptor dynamics.
Main Methods:
- Synthesis of simplified, monocyclic ET-1-derived peptide analogs.
- In vitro pharmacological characterization of peptide analogs, including assessment of G protein signaling and arrestin recruitment.
- Evaluation of receptor activation and selectivity profiles for ETA R and ETB R.
Main Results:
- Novel ET-1 analogs were successfully synthesized, offering an accessible route for peptide drug development.
- Increasing the intramolecular ring size of ET-1 analogs reduced activity at ETA R, promoting selectivity towards ETB R.
- All analogs demonstrated efficient ETB R-mediated signaling via G protein activation and arrestin 3 recruitment, confirming functional integrity.
Conclusions:
- Structural modifications of ET-1 analogs can fine-tune receptor interactions and achieve desired selectivity profiles.
- The developed ET-1 analogs exhibit promising characteristics for targeting the endothelin system in cardiovascular disease treatment.
- Identification of specific residues, like Lys9, enables targeted labeling for novel peptide-mediated shuttling strategies.
Abstract:
Cardiovascular diseases (CVDs) like hypertension are a major cause for death worldwide. In the cardiovascular tissue, the endothelin system-consisting of the receptor subtypes A (ETA R) and B (ETB R) and the mixed agonist endothelin 1 (ET-1)-is a major key player in the regulation of vascular tone and blood pressure. Tight control of this system is required to maintain homeostasis; otherwise, the endothelin system can cause severe CVDs like pulmonary artery hypertension. The high sequence homology between both receptor subtypes limits the development of novel and selective ligands. Identification of small differences in receptor-ligand interactions and determination of selectivity constraints are crucial to fine-tune ligand properties and subsequent signaling events. Here, we report on novel ET-1 analogs and their detailed pharmacological characterization. We generated simplified ET-1-derived monocyclic peptides to provide an accessible synthesis route. By detailed in vitro characterization, we demonstrated that both G protein signaling and the subsequent arrestin recruitment of activated ETB R remain intact, whereas activation of the ETA R depends on the intramolecular ring size. Increasing of the intramolecular ring structure reduces activity at the ETA R and shifts the peptide toward ETB R selectivity. All ET-1 analogs displayed efficient ETB R-mediated signaling by G protein activation and arrestin 3 recruitment. Our study provides in-depth characterization of the ET-1/ETA R and ET-1/ETB R interactions, which has the potential for future development of endothelin-based drugs for CVD treatment. By identification of Lys9 for selective labeling, novel analogs for peptide-mediated shuttling by ET-1 are proposed.
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