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一系列α-螺旋偏向的超短胰高血糖素样肽-1受体激动剂的设计、构效关系及计算模型研究

Design, Structure-Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists.

作者信息

Sawyer Jonathon R, Audie Joseph A, Swanson Jon, Diller David, Santiago Solimar, Gribkoff Valentin K, Ackerman Allison, Hruby Victor J, Gobbo Gianpaolo, Bellucci Michael A, Glauser William A, Pentelute Brad L, Sawyer Tomi K

机构信息

Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA.

Department of Chemistry and Biochemistry, The University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA.

出版信息

Molecules. 2024 Dec 24;30(1):12. doi: 10.3390/molecules30010012.

DOI:10.3390/molecules30010012
PMID:39795070
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11721672/
Abstract

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.

摘要

基于超短胰高血糖素样肽-1（GLP-1）肽H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2，对一系列GLP-1受体（GLP-1R）激动剂进行了系统的构效关系和计算建模分析。这种高效的11肽加深了对线性亲本模板中策略性α-甲基化的α-螺旋偏向的理解，并将GLP-1R激动剂的效力提高了1000倍。这些数据与先前报道的全长GLP-1类似物和与此类超短GLP-1R激动剂肽相关的祖代N端GLP-1片段类似物的共结构相关。此外，本研究描述了用于分析这些发现的定量构效关系（QSAR）模型的开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/9e5bed8f8dd8/molecules-30-00012-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/bcae082138d3/molecules-30-00012-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/b90bb10257dd/molecules-30-00012-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/7920ab1000f5/molecules-30-00012-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/a077ab725c91/molecules-30-00012-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/5b22655dd16a/molecules-30-00012-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/51cc049c3f19/molecules-30-00012-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/7b1b215b878c/molecules-30-00012-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/a91d1add793a/molecules-30-00012-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/9836ebd7d5fa/molecules-30-00012-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/9e5bed8f8dd8/molecules-30-00012-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/bcae082138d3/molecules-30-00012-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/b90bb10257dd/molecules-30-00012-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/7920ab1000f5/molecules-30-00012-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/a077ab725c91/molecules-30-00012-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/5b22655dd16a/molecules-30-00012-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/51cc049c3f19/molecules-30-00012-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/7b1b215b878c/molecules-30-00012-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/a91d1add793a/molecules-30-00012-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/9836ebd7d5fa/molecules-30-00012-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/399d/11721672/9e5bed8f8dd8/molecules-30-00012-g010.jpg

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本文引用的文献

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