Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists
A systematic structure–activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understan...
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2024-12-01
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author | Jonathon R. Sawyer Joseph A. Audie Jon Swanson David Diller Solimar Santiago Valentin K. Gribkoff Allison Ackerman Victor J. Hruby Gianpaolo Gobbo Michael A. Bellucci William A. Glauser Brad L. Pentelute Tomi K. Sawyer |
author_facet | Jonathon R. Sawyer Joseph A. Audie Jon Swanson David Diller Solimar Santiago Valentin K. Gribkoff Allison Ackerman Victor J. Hruby Gianpaolo Gobbo Michael A. Bellucci William A. Glauser Brad L. Pentelute Tomi K. Sawyer |
author_sort | Jonathon R. Sawyer |
collection | DOAJ |
description | A systematic structure–activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understanding of the α-helical bias of strategic α-methylation within the linear parent template as well as optimization of GLP-1R agonist potency by 1000-fold. These data were correlated with previously reported co-structures of both full-length GLP-1 analogs and progenitor N-terminal GLP-1 fragment analogs related to such ultra-short GLP-1R agonist peptides. Furthermore, the development of a quantitative structure–activity relationship (QSAR) model to analyze these findings is described in this study. |
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id | doaj-art-1730b9e344e744a88edf8e6f7a6f474d |
institution | Kabale University |
issn | 1420-3049 |
language | English |
publishDate | 2024-12-01 |
publisher | MDPI AG |
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series | Molecules |
spelling | doaj-art-1730b9e344e744a88edf8e6f7a6f474d2025-01-10T13:18:35ZengMDPI AGMolecules1420-30492024-12-013011210.3390/molecules30010012Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor AgonistsJonathon R. Sawyer0Joseph A. Audie1Jon Swanson2David Diller3Solimar Santiago4Valentin K. Gribkoff5Allison Ackerman6Victor J. Hruby7Gianpaolo Gobbo8Michael A. Bellucci9William A. Glauser10Brad L. Pentelute11Tomi K. Sawyer12Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USAEudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USAEudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USAEudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USAResolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USAResolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USAResolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USADepartment of Chemistry and Biochemistry, The University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USAXtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USAXtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USAXtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USAResolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USAResolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USAA systematic structure–activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understanding of the α-helical bias of strategic α-methylation within the linear parent template as well as optimization of GLP-1R agonist potency by 1000-fold. These data were correlated with previously reported co-structures of both full-length GLP-1 analogs and progenitor N-terminal GLP-1 fragment analogs related to such ultra-short GLP-1R agonist peptides. Furthermore, the development of a quantitative structure–activity relationship (QSAR) model to analyze these findings is described in this study.https://www.mdpi.com/1420-3049/30/1/12glucagon-like peptide-1 (GLP-1)Cα-methylation<i>p</i>-phenyl-phenylalanine (Bip)2-amino-isobutyric acid (Aib)α-methyl-phenylalanine (α-MePhe)α-methyl-phenylalanine [2-F] (α-MePhe[2-F]) |
spellingShingle | Jonathon R. Sawyer Joseph A. Audie Jon Swanson David Diller Solimar Santiago Valentin K. Gribkoff Allison Ackerman Victor J. Hruby Gianpaolo Gobbo Michael A. Bellucci William A. Glauser Brad L. Pentelute Tomi K. Sawyer Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists Molecules glucagon-like peptide-1 (GLP-1) Cα-methylation <i>p</i>-phenyl-phenylalanine (Bip) 2-amino-isobutyric acid (Aib) α-methyl-phenylalanine (α-MePhe) α-methyl-phenylalanine [2-F] (α-MePhe[2-F]) |
title | Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists |
title_full | Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists |
title_fullStr | Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists |
title_full_unstemmed | Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists |
title_short | Design, Structure–Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists |
title_sort | design structure activity relationships and computational modeling studies of a series of α helix biased ultra short glucagon like peptide 1 receptor agonists |
topic | glucagon-like peptide-1 (GLP-1) Cα-methylation <i>p</i>-phenyl-phenylalanine (Bip) 2-amino-isobutyric acid (Aib) α-methyl-phenylalanine (α-MePhe) α-methyl-phenylalanine [2-F] (α-MePhe[2-F]) |
url | https://www.mdpi.com/1420-3049/30/1/12 |
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