Hellmuth Nadine, Brat Camilla, Awad Omar, George Sven, Kahnt Astrid, Bauer Tom, Huynh Phuoc Hai Phong, Steinhilber Dieter, Angioni Carlo, Hassan Mohamed, Hock Katharina J, Manolikakes Georg, Zacharowski Kai, Roos Jessica, Maier Thorsten J
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
Front Pharmacol. 2021 Nov 18;12:715076. doi: 10.3389/fphar.2021.715076. eCollection 2021.
Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects and selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure-activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.
内源性硝基脂肪酸（NFA）是一类具有强大亲电活性的脂质介质，可发挥生物学效应并对含硫醇的靶蛋白进行选择性共价修饰。在由靶向蛋白硝基烷基化引起的疾病动物模型中，NFA的细胞保护、抗炎和抗肿瘤作用是未来开发抗炎和抗肿瘤药物的重要基础。考虑到疾病的复杂性以及伴随的合并症，临床上迫切需要有效的多功能药物。NFA由含有硝基烯烃部分的脂肪酸主链组成，可引发迈克尔加成反应。然而，对于不同NFA靶点的靶标特异性构效关系和选择性，人们了解较少。因此，我们分析了15种NFA衍生物，并将它们与先导结构9-硝基油酸（9NOA）在抑制NF-κB（核因子κB）信号传导、诱导Nrf-2（核因子红细胞2相关因子2）基因表达、抑制sEH（可溶性环氧化物水解酶）、LO（脂氧合酶）和COX-2（环氧化酶-2）以及对结肠癌细胞的细胞毒性作用方面进行了比较。对迈克尔受体位置的微小修饰和链长的变化导致药物表现出更高的靶点偏好性或增强的多靶点作用，部分药物的效力高于9NOA。这项研究朝着更好地理解NFA的生物学特性及其作为设计未来抗炎药物支架的巨大潜力迈出了重要一步。
