Using conformational constraints at position 6 of Angiotensin II to generate compounds with enhanced AT2R selectivity and proteolytic stability

Dirk Tourwé; Antonis D Tsiailanis; Nikolaos Parisis; Baydaa Hirmiz; Mark Del Borgo; Marie-Isabel Aguilar; Olivier Van der Poorten; Steven Ballet; Robert E Widdop; Andreas G Tzakos

doi:10.1016/j.bmcl.2021.128086

Using conformational constraints at position 6 of Angiotensin II to generate compounds with enhanced AT2R selectivity and proteolytic stability

Bioorg Med Chem Lett. 2021 Jul 1:43:128086. doi: 10.1016/j.bmcl.2021.128086. Epub 2021 May 7.

Affiliations

¹ Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: datourwe@vub.be.
² Laboratory of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina 45110, Greece.
³ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
⁴ Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.
⁵ Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
⁶ Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: Steven.Ballet@vub.be.
⁷ Laboratory of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina 45110, Greece; University Research Center of Ioannina (URCI), Institute of Materials Science and Computing, Ioannina, Greece. Electronic address: atzakos@uoi.gr.

PMID: 33965531
DOI: 10.1016/j.bmcl.2021.128086

Abstract

The Renin-Angiotensin System (RAS) plays a crucial role in numerous pathological conditions. Two of the critical RAS players, the angiotensin receptors AT1R and AT2R, possess differential functional profiles, although they share high sequence similarity. Although the main focus has been placed on AT1R, several epidemiological studies have evidenced that activation of AT2R could operate as a multimodal therapeutic target for different diseases. Thus, the development of selective AT2R ligands could have a high clinical potential for different therapeutic directions. Furthermore, they could serve as a powerful tool to interrogate the molecular mechanisms that are mediated by AT2R. Based on our recently established high affinity and AT2R selective compound [Y]⁶-AII we developed several analogues through modifying aminoacids located at positions 6 and 7 with various conformationally constrained analogues to enhance both the selectivity and stability. We report the development of high-affinity AT2R binders, which displayed high selectivity for AT2R versus AT1R. Furthermore, all analogues presented enhanced stability in human plasma with respect to the parent hormone Angiotensin II as also [Y]⁶-AII.

Keywords: Angiotensin II; Constrained peptides; Proteolytic stability; Receptor affinity; Receptor selectivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II / analogs & derivatives
Angiotensin II / chemistry
Angiotensin II / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Conformation
Proteolysis / drug effects
Receptor, Angiotensin, Type 2 / metabolism*
Structure-Activity Relationship

Substances

Receptor, Angiotensin, Type 2
Angiotensin II