多肽药物的骨架修饰改变了其在体内的作用持续时间。
Backbone modification of a polypeptide drug alters duration of action in vivo.
机构信息
Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
出版信息
Nat Biotechnol. 2014 Jul;32(7):653-5. doi: 10.1038/nbt.2920. Epub 2014 Jun 15.
Abstract
Systematic modification of the backbone of bioactive polypeptides through β-amino acid residue incorporation could provide a strategy for generating molecules with improved drug properties, but such alterations can result in lower receptor affinity and potency. Using an agonist of parathyroid hormone receptor-1 (PTHR1), a G protein-coupled receptor in the B-family, we present an approach for α→β residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.
摘要
通过在生物活性多肽骨架中引入β-氨基酸残基进行系统修饰，可以为生成具有改善的药物性质的分子提供一种策略，但这种改变可能导致受体亲和力和效力降低。我们使用甲状旁腺激素受体 1（PTHR1）的激动剂，即 B 族 G 蛋白偶联受体，提出了一种α→β残基替换的方法，使体内具有高活性和改善的药代动力学性质。
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本文引用的文献
1
A β-peptide agonist of the GLP-1 receptor, a class B GPCR.GLP-1 受体的 β-肽激动剂，B 类 G 蛋白偶联受体。
Org Lett. 2013 Oct 18;15(20):5318-21. doi: 10.1021/ol402568j. Epub 2013 Oct 2.
2
α-Helix mimicry with α/β-peptides.用α/β肽模拟α-螺旋
Methods Enzymol. 2013;523:407-29. doi: 10.1016/B978-0-12-394292-0.00019-9.
3
Evaluation of diverse α/β-backbone patterns for functional α-helix mimicry: analogues of the Bim BH3 domain.评估不同的 α/β-骨架模式以模拟功能 α-螺旋：Bim BH3 结构域类似物。
J Am Chem Soc. 2012 Jan 11;134(1):315-23. doi: 10.1021/ja207148m. Epub 2011 Dec 8.
4
The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatide acetate in rats.肝脏和肾脏在大鼠皮下注射醋酸特立帕肽药代动力学中的作用
Xenobiotica. 2012 Apr;42(4):398-407. doi: 10.3109/00498254.2011.622811. Epub 2011 Oct 24.
5
A luminescent biosensor with increased dynamic range for intracellular cAMP.一种具有更大动态范围的用于细胞内 cAMP 的荧光生物传感器。
ACS Chem Biol. 2011 Nov 18;6(11):1193-7. doi: 10.1021/cb200248h. Epub 2011 Sep 22.
6
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Nat Chem Biol. 2011 May;7(5):278-84. doi: 10.1038/nchembio.545. Epub 2011 Mar 27.
7
Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm.甲状旁腺激素受体信号转导和运输的分子基础：B 族 G 蛋白偶联受体范例。
Cell Mol Life Sci. 2011 Jan;68(1):1-13. doi: 10.1007/s00018-010-0465-9. Epub 2010 Aug 12.
8
Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor.胰高血糖素样肽-1 与胰高血糖素样肽-1 受体胞外结构域复合物的晶体结构
J Biol Chem. 2010 Jan 1;285(1):723-30. doi: 10.1074/jbc.M109.033829. Epub 2009 Oct 27.
9
Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.α/β-肽折叠体对蛋白质表面识别的结构与生物学模拟
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14751-6. doi: 10.1073/pnas.0902663106. Epub 2009 Aug 17.
10
Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation.通过靶向特定受体构象的肽配体在甲状旁腺激素受体处进行长时间信号传导。
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16525-30. doi: 10.1073/pnas.0808750105. Epub 2008 Oct 22.
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