Suto Mark J, Gupta Vandana, Mathew Bini, Zhang Wei, Pallero Manuel A, Murphy-Ullrich Joanne E
Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35205, United States.
Department of Pathology, University of Alabama at Birmingham, VH G001A, 1720 Second Avenue South, Birmingham, Alabama 35294, United States.
ACS Med Chem Lett. 2020 May 7;11(6):1130-1136. doi: 10.1021/acsmedchemlett.9b00540. eCollection 2020 Jun 11.
TGF-β has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-β include antagonists of the active ligand or TGF-β receptor kinase activity. These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-β are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-β complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 (), is effective but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 () with a single chiral center, which blocks TGF-β activation (pIC = 8.12 nM) and has a plasma half life of 1.8 h (iv).
转化生长因子-β（TGF-β）一直是治疗纤维化疾病和某些癌症的关注靶点。靶向TGF-β的方法包括活性配体拮抗剂或TGF-β受体激酶活性拮抗剂。由于缺乏有效性和治疗窗口有限，这些方法在临床试验中失败了。在这种情况下，需要更新的、更具选择性的靶向TGF-β的方法。我们之前报道过，基质细胞蛋白血小板反应蛋白1可激活潜伏的TGF-β复合物，并且在各种动物模型中使用三肽/四肽拮抗该途径可减少纤维化。三肽SRI-31277（）有效，但血浆半衰期较短（0.2小时）。在此，我们描述了SRI-31277类似物的设计与合成，特别是保留效力并具有改善的生物利用度的更小的肽。我们鉴定出具有单一手性中心的SRI-35241（），它可阻断TGF-β激活（pIC = 8.12 nM），静脉注射时血浆半衰期为1.8小时。
