Wang Guankai, Wang Jingjing, Du Lupei, Li Minyong
Key Laboratory of Chemical Biology (MOE), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Chem. 2022 Jan 28;9:809495. doi: 10.3389/fchem.2021.809495. eCollection 2021.
The main effect of Vanin-1/VNN1 is related to its pantetheinase sulfhydrylase activity, which can hydrolyze pantetheine into pantothenic acid and cysteamine. In recent studies, the enzymatic activity of vanin-1/VNN1 has been found to be essential in the development of many diseases. The study of specific vanin-1/VNN1 inhibitors can give us a deeper understanding of its role in the disease process. In this study, different skeletal inhibitors were designed and synthesized using pyrimidine amide compounds as lead compounds. In order to screen inhibitors intuitively, a fluorescent probe PA-AFC for evaluation of inhibitors was designed and synthesized in this study, which has good sensitivity and specificity. The bioluminescent probe PA-AL was then used for cellular level and inhibitor evaluation. This screening method was convenient, economical and highly accurate. Finally, these inhibitors were applied to a mouse colitis model, confirming that vanin-1 is useful in IBD and providing a new therapeutic direction.
泛酰巯基乙胺酶-1（Vanin-1/VNN1）的主要作用与其泛酰巯基乙胺酶巯基水解酶活性有关，该活性可将泛酰巯基乙胺水解为泛酸和半胱胺。在最近的研究中，已发现泛酰巯基乙胺酶-1（Vanin-1/VNN1）的酶活性在许多疾病的发展过程中至关重要。对特定的泛酰巯基乙胺酶-1（Vanin-1/VNN1）抑制剂的研究可以让我们更深入地了解其在疾病过程中的作用。在本研究中，以嘧啶酰胺类化合物为先导化合物设计并合成了不同的骨架抑制剂。为了直观地筛选抑制剂，本研究设计并合成了一种用于评估抑制剂的荧光探针PA-AFC，其具有良好的灵敏度和特异性。然后将生物发光探针PA-AL用于细胞水平和抑制剂评估。这种筛选方法方便、经济且高度准确。最后，将这些抑制剂应用于小鼠结肠炎模型，证实泛酰巯基乙胺酶-1（Vanin-1）在炎症性肠病（IBD）中具有作用，并提供了新的治疗方向。
