Chauvel E N, Llorens-Cortès C, Coric P, Wilk S, Roques B P, Fournié-Zaluski M C
Unité de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D 1500 CNRS, Paris, France.
J Med Chem. 1994 Sep 2;37(18):2950-7. doi: 10.1021/jm00044a016.
Aminopeptidase A (APA) is a highly selective peptidase, which cleaves the N-terminal Glu or Asp residues of biologically active peptides, and has therefore been proposed to be involved in angiotensin II and CCK8 metabolism. Highly potent and selective APA inhibitors are consequently required to study the physiological regulation of these two peptides. Using, as a model, Glu-thiol (4-amino-5-mercaptopentanoic acid), which was the first efficient APA inhibitor described but is however equipotent on APA (0.14 microM) and aminopeptidase N (APN) (0.12 microM), several beta-amino thiol inhibitors have been synthesized. In these molecules, the length of the side chain was varied and the carboxylate group of Glu-thiol was replaced by other negatively charged groups, such as phosphonate, sulfonate, hydroxamate, and thiol. The inhibitory potency of one of these compounds, 22h (S)-3-amino-4-mercaptobutanesulfonate, was found to be nearly 100-fold better for APA than for APN, with an affinity (0.29 microM) almost equivalent to that of Glu-thiol. Hence, this compound is the first selective APA inhibitor reported, and as such, it should be an interesting probe to explore the physiological involvement of APA in the metabolism of neuropeptides like angiotensin II and CCK8.
氨肽酶A（APA）是一种高度选择性的肽酶，可切割生物活性肽的N端谷氨酸或天冬氨酸残基，因此有人提出它参与血管紧张素II和CCK8的代谢。因此，需要高效且选择性的APA抑制剂来研究这两种肽的生理调节。以Glu-硫醇（4-氨基-5-巯基戊酸）为模型，它是最早描述的有效APA抑制剂，但对APA（0.14 microM）和氨肽酶N（APN）（0.12 microM）的效力相同，已合成了几种β-氨基硫醇抑制剂。在这些分子中，侧链长度不同，Glu-硫醇的羧酸盐基团被其他带负电荷的基团取代，如膦酸盐、磺酸盐、异羟肟酸盐和硫醇。发现其中一种化合物22h（S）-3-氨基-4-巯基丁磺酸盐对APA的抑制效力比对APN高近100倍，其亲和力（0.29 microM）几乎与Glu-硫醇相当。因此，该化合物是首个报道的选择性APA抑制剂，就此而言，它应该是探索APA在血管紧张素II和CCK8等神经肽代谢中的生理作用的有趣探针。
