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3 results on '"Competition-binding experiments"'

1. Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity.

Author

Vrettos, Eirinaios I., Valverde, Ibai E., Mascarin, Alba, Pallier, Patrick N., Cerofolini, Linda, Fragai, Marco, Parigi, Giacomo, Hirmiz, Baydaa, Bekas, Nick, Grob, Nathalie M., Stylos, Evgenios Κ., Shaye, Hamidreza, Del Borgo, Mark, Aguilar, Marie‐Isabel, Magnani, Francesca, Syed, Nelofer, Crook, Timothy, Waqif, Emal, Ghazaly, Essam, and Cherezov, Vadim

Subjects
*SPINE, *ANGIOTENSINS, *PEPTIDE bonds, *NUCLEAR magnetic resonance spectroscopy, *AMINO acids, *ANGIOTENSIN II
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 Towards this end, four [Y]6‐Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4‐disubstituted 1,2,3‐triazole isosteres in four different backbone locations.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. [ABSTRACT FROM AUTHOR]

Published
2020
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2. Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

Author

Mark P. Del Borgo, Ibai E. Valverde, Linda Cerofolini, Alba Mascarin, Hamidreza Shaye, Adina T. Michael-Titus, Claudio Luchinat, Vadim Cherezov, Francesca Magnani, Essam Ghazaly, Patrick N. Pallier, Marco Fragai, Andreas G. Tzakos, Thomas L. Mindt, Nelofer Syed, Marie-Isabel Aguilar, Eirinaios I. Vrettos, Nathalie M. Grob, Evgenios Κ. Stylos, Tim Crook, Robert E Widdop, Nick Bekas, Emal Waqif, Baydaa Hirmiz, Giacomo Parigi, Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Barrow Foundation UK, Brain Tumour Research Campaign, and Brain Tumour Research

Subjects
Peptidomimetic, Stereochemistry, Chemistry, Multidisciplinary, [SDV]Life Sciences [q-bio], G-protein-coupled receptors, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Ligands, Click chemistry, Competition-binding experiments, Neurotrophic effects, Peptidomimetics, 010402 general chemistry, 01 natural sciences, Catalysis, Substrate Specificity, neurotrophic effects, competition-binding experiments, Animals, Humans, Peptide bond, Amino Acids, ComputingMilieux_MISCELLANEOUS, G protein-coupled receptor, chemistry.chemical_classification, Receptors, Angiotensin, Science & Technology, Angiotensin II receptor type 1, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Angiotensin II, Organic Chemistry, General Chemistry, 0104 chemical sciences, Amino acid, Chemistry, HEK293 Cells, chemistry, peptidomimetics, Mutation, Physical Sciences, click chemistry, Peptides, 03 Chemical Sciences, Two-dimensional nuclear magnetic resonance spectroscopy
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. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. ISSN:0947-6539 ISSN:1521-3765

Published
2020
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3. Cover Feature: Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity (Chem. Eur. J. 47/2020).

Author

Vrettos, Eirinaios I., Valverde, Ibai E., Mascarin, Alba, Pallier, Patrick N., Cerofolini, Linda, Fragai, Marco, Parigi, Giacomo, Hirmiz, Baydaa, Bekas, Nick, Grob, Nathalie M., Stylos, Evgenios Κ., Shaye, Hamidreza, Del Borgo, Mark, Aguilar, Marie‐Isabel, Magnani, Francesca, Syed, Nelofer, Crook, Timothy, Waqif, Emal, Ghazaly, Essam, and Cherezov, Vadim

Subjects
*ANGIOTENSINS, *SPINE, *CLICK chemistry, *CHEMISTRY experiments
Published
2020
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