Sarah C Erlandson, Jialu Wang, Haoran Jiang, James Osei-Owusu, Howard A Rockman, Andrew C Kruse
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引用次数: 0
摘要
松弛素-2 是一种肽类激素,在人类心血管和生殖生物学中发挥着重要作用。它能够激活细胞反应,如血管扩张、血管生成、抗炎和抗纤维化作用,因此人们对使用松弛素-2 作为心力衰竭和多种纤维化病症的疗法产生了浓厚的兴趣。然而,重组弛缓素-2 的血清半衰期很短,限制了其临床应用。在此,我们介绍了针对松弛素-2 激素的蛋白质工程学研究,目的是延长其血清半衰期,同时保持其激活 G 蛋白偶联受体 RXFP1 的能力。为此,我们优化了弛缓素-2 与抗体 Fc 片段的融合,生成的激素在小鼠体内的循环半衰期约为 3 到 5 天,同时在体外和体内都能保持对 RXFP1 受体的强效激动活性。
Engineering and Characterization of a Long-Half-Life Relaxin Receptor RXFP1 Agonist.
Relaxin-2 is a peptide hormone with important roles in human cardiovascular and reproductive biology. Its ability to activate cellular responses such as vasodilation, angiogenesis, and anti-inflammatory and antifibrotic effects has led to significant interest in using relaxin-2 as a therapeutic for heart failure and several fibrotic conditions. However, recombinant relaxin-2 has a very short serum half-life, limiting its clinical applications. Here, we present protein engineering efforts targeting the relaxin-2 hormone in order to increase its serum half-life while maintaining its ability to activate the G protein-coupled receptor RXFP1. To achieve this, we optimized a fusion between relaxin-2 and an antibody Fc fragment, generating a version of the hormone with a circulating half-life of around 3 to 5 days in mice while retaining potent agonist activity at the RXFP1 receptor both in vitro and in vivo.
期刊介绍:
Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development.
Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.