Backbone modification of a polypeptide drug alters duration of action in vivo

被引：94
作者：
Cheloha, Ross W. [1 ]
Maeda, Akira [2 ,3 ]
Dean, Thomas [2 ,3 ]
Gardella, Thomas J. [2 ,3 ]
Gellman, Samuel H. [1 ]
机构：
[1] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA
[2] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA
[3] Harvard Univ, Sch Med, Boston, MA USA
来源：
NATURE BIOTECHNOLOGY | 2014年 / 32卷 / 07期
基金：
美国国家卫生研究院;
关键词：
ALPHA-HELIX MIMICRY; AMINO-ACID RESIDUES; PARATHYROID-HORMONE; RECEPTOR CONFORMATION; PROTEIN; PEPTIDES; ANALOGS; RECOGNITION; MECHANISM; CAMP;
D O I：
10.1038/nbt.2920
中图分类号：
Q81 [生物工程学（生物技术）]; Q93 [微生物学];
学科分类号：
071005 ; 0836 ; 090102 ; 100705 ;
摘要：
Systematic modification of the backbone of bioactive polypeptides through beta-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 alpha ->beta residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.
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收藏
页码：653 / +
页数：4
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