Papakyriakou Athanasios, Zervoudi Efthalia, Tsoukalidou Sofia, Mauvais Francois-Xavier, Sfyroera Georgia, Mastellos Dimitrios C, van Endert Peter, Theodorakis Emmanuel A, Vourloumis Dionisios, Stratikos Efstratios
National Center for Scientific Research "Demokritos" , Aghia Paraskevi, 15310 Athens, Greece.
J Med Chem. 2015 Feb 12;58(3):1524-43. doi: 10.1021/jm501867s. Epub 2015 Jan 30.
Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.
M1氨肽酶的催产素酶亚家族成员（内质网氨肽酶1、内质网氨肽酶2和胰岛素调节氨肽酶）在人类适应性免疫反应和先天性免疫反应中均发挥重要作用。它们的酶活性可能导致从病毒和寄生虫感染到自身免疫及癌症等多种主要人类疾病的发病机制。我们之前已证明二氨基苯甲酸衍生物有望作为这类氨肽酶的选择性抑制剂。在本研究中，我们深入探究了一系列3,4 - 二氨基苯甲酸衍生物作为这类酶的抑制剂，获得了内质网氨肽酶2（IC50 = 237 nM）和胰岛素调节氨肽酶（IC50 = 105 nM）的亚微摩尔级抑制剂。基于细胞的分析表明，先导化合物可有效下调由脂多糖和干扰素 - γ诱导的巨噬细胞活化以及骨髓来源树突状细胞的交叉呈递。我们的结果表明，这类抑制剂可能有助于靶向性下调免疫反应。
