Novo Nordisk China R&D, 29 Life Science Park Road, Beijing, China.
Protein Eng Des Sel. 2011 Nov;24(11):855-60. doi: 10.1093/protein/gzr047. Epub 2011 Sep 27.
Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.
催乳素（PRL）是乳腺上皮强有力的生长刺激因子，被认为是导致乳腺癌和前列腺癌发展和进展的因素之一。在过去的几十年中，已经鉴定出几种催乳素受体（PRLR）拮抗剂，但由于受体亲和力低，它们在体内的生长抑制效力受到限制，因此在药理学上不适合临床治疗。因此，提高受体亲和力对于开发具有改善体内效力的改良 PRLR 拮抗变异体至关重要。在这项研究中，我们生成了人 G129R-PRL 突变体的 Site1 聚焦蛋白文库，并筛选出对人 PRLR 亲和力增加的文库。通过将这些突变与增强的 PRLR 亲和力相结合，我们鉴定出一种新型 G129R-PRL 变体，其 Site1 上的突变使体外拮抗效力增加近 50 倍。
