Mycophenolate mofetil is an established anti-proliferative and immune-suppressive agent that minimizes the proliferation of inflammatory cells by interfering with nucleic acid synthesis. Herein, we report our discovery of the prostaglandin inhibiting properties of MMF, which offers new applications for the drug in the treatment of inflammatory diseases. The estimated values of IC50MMFCOX-1, IC50MMFCOX-2, and IC50MMF5-LOX were 5.53, 0.19, and 4.47 µM, respectively. In contrast, mycophenolic acid (MPA) showed slightly stronger inhibition: IC50MPACOX-1, IC50MPACOX-2, and IC50MPA5-LOX were 4.62, 0.14, and 4.49 µM, respectively. These results indicate that MMF and MPA are, respectively, 28.6 and 33 times more selective for cyclooxygenase-2 than for cyclooxygenase-1, which implies that MMF would have less impact on the gastric mucosa than most nonselective, nonsteroidal anti-inflammatory drugs. Furthermore, MMF provided dose-dependent relief of acute inflammation in the carrageenan-induced rat paw edema test, with results comparable to those of celecoxib and indomethacin. Molecular dynamics simulations indicated that the MMF bond with COX-2 was stable, as evidenced by a low root-mean-square deviation of atomic positions, complementary per-residue root-mean-square fluctuation, and 0–4 hydrogen bonds during the 50-ns simulation time. Therefore, MMF provides immune-suppressing, cyclooxygenase-inhibiting, and inflammation-relieving properties. Our results indicate that MMF can be 1) repositioned for inflammation treatment without the need for further expensive clinical trials, 2) used for local acute inflammations, and 3) used as a sparing agent for other steroid and non-steroid anti-inflammatory medications, especially in topical applications.

中文翻译：

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霉酚酸酯通过抑制前列腺素合酶抑制炎症：分子和实验药物再利用的研究

霉酚酸酯是一种成熟的抗增殖和免疫抑制剂，可通过干扰核酸合成来最大程度地减少炎症细胞的增殖。在此，我们报告了我们对MMF的前列腺素抑制特性的发现，这为该药物在炎性疾病的治疗中提供了新的应用。IC50MMFCOX-1，IC50MMFCOX-2和IC50MMF5-LOX的估计值分别为5.53、0.19和4.47 µM。相反，霉酚酸（MPA）的抑制作用稍强：IC50MPACOX-1，IC50MPACOX-2和IC50MPA5-LOX分别为4.62、0.14和4.49 µM。这些结果表明，MMF和MPA对环氧合酶2的选择性分别是对环氧合酶1的28.6和33倍，这意味着MMF对胃粘膜的影响要比大多数非选择性，非甾体类抗炎药小。此外，MMF在角叉菜胶诱发的大鼠爪水肿试验中提供了剂量依赖性的急性炎症缓解，其结果可与塞来昔布和消炎痛相媲美。分子动力学模拟表明，与COX-2的MMF键是稳定的，这在50年代中原子位置的均方根偏差低，互补的每个残基均方根波动以及0–4个氢键中得到了证明。 -ns模拟时间。因此，MMF具有抑制免疫，抑制环氧合酶和减轻炎症的特性。我们的结果表明，MMF可以1）重新定位以进行炎症治疗，而无需进行进一步的昂贵的临床试验，