Department of Chemistry, Washington State University, Pullman, WA, 99164-4630, USA.
Chem Biol Drug Des. 2013 Nov;82(5):612-9. doi: 10.1111/cbdd.12174. Epub 2013 Sep 25.
Glutamate carboxypeptidase II (GCPII) is a membrane-bound cell surface peptidase. There is significant interest in the inhibition of GCPII as a means of neuroprotection, while GCPII inhibition as a method to treat prostate cancer remains a topic of further investigation. The key zinc-binding functional group of the well-characterized classes of GCPII inhibitors (phosphonates and phosphoramidates) is tetrahedral and negatively charged at neutral pH, while glutamyl urea class of inhibitors possesses a planar and neutral zinc-binding group. This study explores a new class of GCPII inhibitors, glutamyl sulfamides, which possess a putative net neutral tetrahedral zinc-binding motif. A small library containing six sulfamides was prepared and evaluated for inhibitory potency against purified GCPII in an enzymatic assay. While most inhibitors have potencies in the micromolar range, one showed promising sub-micromolar potency, with the optimal inhibitor in this series being aspartyl-glutamyl sulfamide (2d). Lastly, computational docking was used to develop a tentative binding model on how the most potent inhibitors interact with the ligand-binding site of GCPII.
谷氨酸羧肽酶 II（GCPII）是一种膜结合的细胞表面肽酶。抑制 GCPII 作为神经保护的一种手段引起了广泛关注，而 GCPII 抑制作为治疗前列腺癌的一种方法仍在进一步研究中。经过充分研究的 GCPII 抑制剂（膦酸酯和磷酰胺酯）的典型锌结合功能基团为四面体，在中性 pH 下带负电荷，而谷氨酸酰脲类抑制剂具有平面中性锌结合基团。本研究探索了一类新的 GCPII 抑制剂——谷氨酰磺酰胺，其具有假定的净中性四面体锌结合基序。合成了一个包含六个磺酰胺的小文库，并在酶促测定中评估了它们对纯化的 GCPII 的抑制活性。虽然大多数抑制剂的活性在微摩尔范围内，但有一种抑制剂表现出有希望的亚微摩尔活性，该系列中最佳抑制剂是天冬氨酰-谷氨酸磺酰胺（2d）。最后，通过计算对接来建立一个关于最有效抑制剂如何与 GCPII 的配体结合位点相互作用的暂定结合模型。
