National Centre for Scientific Research "Demokritos", Ag. Paraskevi, GR-15341 Athens, Greece.
Department of Pharmacy, University of Patras, 26504 Patra, Greece.
J Med Chem. 2022 Jul 28;65(14):10098-10117. doi: 10.1021/acs.jmedchem.2c00904. Epub 2022 Jul 14.
The oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the α-hydroxy-β-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that α-hydroxy-β-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases.
M1 锌氨肽酶的oxytocinase 亚家族包含新兴的药物靶点，包括驻留在内质网的氨肽酶 1 和 2（ERAP1 和 ERAP2）和胰岛素调节氨肽酶（IRAP）；然而，关于临床相关抑制剂的报道很有限。在这里，我们报告了一种新的高非对映选择性和区域选择性的合成方法，用于对 bestatin 的 α-羟基-β-氨基酸支架进行功能化。通过高分辨率 ERAP1 与微摩尔抑制剂复合物的 X 射线晶体结构研究了立体化学和抑制机制。通过探索 P1 侧链功能，我们实现了显著的效力和选择性，并报告了一种细胞活性的、低纳摩尔的 IRAP 抑制剂，对同源酶具有 >120 倍的选择性。与该抑制剂结合的 IRAP 的 X 射线晶体结构分析表明，与 GAMEN 环的相互作用是效力和选择性的一个未被充分认识的关键决定因素。总的来说，我们的结果表明，α-羟基-β-氨基酸衍生物可能成为这组氨肽酶的有用化学工具和药物先导物。
