23
IRUS Total
Downloads
  Altmetric

Single peptide backbone surrogate mutations to regulate Angiotensin GPCR subtype selectivity

File Description SizeFormat 
Vrettosetal.2020.pdfAccepted version1.25 MBAdobe PDFView/Open
Title: Single peptide backbone surrogate mutations to regulate Angiotensin GPCR subtype selectivity
Authors: Vrettos, E
Valverde, IE
Mascarin, A
Pallier, PN
Cerofolini, L
Fragai, M
Parigi, G
Hirmiz, B
Bekas, N
Grob, NM
Shaye, H
Del Borgo, M
Aguilar, M
Magnani, F
Syed, N
Crook, T
Waqif, E
Ghazaly, E
Cherezov, V
Widdop, RE
Luchinat, C
MichaelTitus, AT
Mindt, TL
Tzakos, AG
Stylos, EK
Item Type: Journal Article
Abstract: Mutating the side‐chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half‐life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6‐Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4‐disubstituted 1,2,3‐triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross‐peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21.
Issue Date: 21-Aug-2020
Date of Acceptance: 31-Mar-2020
URI: http://hdl.handle.net/10044/1/82275
DOI: 10.1002/chem.202000924
ISSN: 0947-6539
Publisher: Wiley
Start Page: 10690
End Page: 10694
Journal / Book Title: Chemistry: A European Journal
Volume: 26
Issue: 47
Copyright Statement: © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article, which has been published in final form at https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/chem.202000924. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Sponsor/Funder: Barrow Foundation UK
Brain Tumour Research Campaign
Brain Tumour Research
Funder's Grant Number: N/A
N/A
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
click chemistry
competition-binding experiments
G-protein-coupled receptors
neurotrophic effects
peptidomimetics
PEPTIDOMIMETICS
G-protein-coupled receptors
click chemistry
competition-binding experiments
neurotrophic effects
peptidomimetics
Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
click chemistry
competition-binding experiments
G-protein-coupled receptors
neurotrophic effects
peptidomimetics
PEPTIDOMIMETICS
General Chemistry
03 Chemical Sciences
Publication Status: Published
Online Publication Date: 2020-05-04
Appears in Collections:Department of Brain Sciences