Chuong Patrick, Statsyuk Alexander
bioRxiv. 2023 Oct 14:2023.10.14.562361. doi: 10.1101/2023.10.14.562361.
Smurf1 is a HECT E3 ligase that is genetically micro-duplicated in human patients and is associated with osteoporosis. Smurf1 mice on the other hand show an increase in bone density as they age, while being viable and fertile. Therefore, Smurf1 is a promising drug target to treat osteoporosis. This paper reports the discovery, synthesis, and biochemical characterization of highly selective Smurf1 inhibitors. We show that these compounds inhibit the catalytic HECT domain of Smurf1 with 500 nM IC , but they do not inhibit closely related Smurf2 ligase, which is 80% identical to Smurf1. We show that Smurf1 inhibitors act by preventing the trans-thiolation reaction between Smurf1 and E2∼Ub thioesters. Our preliminary studies show that the C-lobe of Smurf1 alone does not contribute to the observed high selectivity of Smurf1 inhibitors.
Smurf1是一种HECT E3连接酶，在人类患者中存在基因微重复，且与骨质疏松症相关。另一方面，Smurf1基因敲除小鼠随着年龄增长骨密度增加，且具有生存能力和繁殖能力。因此，Smurf1是治疗骨质疏松症的一个有前景的药物靶点。本文报道了高选择性Smurf1抑制剂的发现、合成及生化特性。我们表明，这些化合物以500 nM的半数抑制浓度（IC₅₀）抑制Smurf1的催化HECT结构域，但不抑制与Smurf1有80%同源性的密切相关的Smurf2连接酶。我们表明，Smurf1抑制剂通过阻止Smurf1与E2~泛素硫酯之间的转硫醇化反应起作用。我们的初步研究表明，单独的Smurf1的C结构域对观察到的Smurf1抑制剂的高选择性没有贡献。
