Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, United States.
Mol Pharm. 2024 Sep 2;21(9):4441-4449. doi: 10.1021/acs.molpharmaceut.4c00368. Epub 2024 Aug 12.
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.
松弛素-2 是一种肽激素，在人类心血管和生殖生物学中具有重要作用。其激活细胞反应的能力，如血管舒张、血管生成、抗炎和抗纤维化作用，使得松弛素-2 作为心力衰竭和几种纤维化疾病的治疗药物引起了广泛关注。然而，重组松弛素-2 的血清半衰期非常短，限制了其临床应用。在这里，我们介绍了针对松弛素-2 激素的蛋白质工程努力，以增加其血清半衰期，同时保持其激活 G 蛋白偶联受体 RXFP1 的能力。为了实现这一目标，我们优化了松弛素-2 与抗体 Fc 片段之间的融合，生成了一种在小鼠体内半衰期约为 3 至 5 天的激素版本，同时在体外和体内保留了对 RXFP1 受体的强效激动剂活性。
