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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Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2024-12-01
Series:Molecules
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Online Access:https://www.mdpi.com/1420-3049/30/1/12
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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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publishDate 2024-12-01
publisher MDPI AG
record_format Article
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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