PYR-41 is an irreversible, cell-permeable inhibitor of ubiquitin-activating enzyme E1, with an IC50 value less than 10μM and minimal effects on E2 and E3[1, 2]. PYR-41 selectively and irreversibly binds to the cysteine residue of E1, effectively blocking the formation of the thioester bond between ubiquitin and E1, thereby inhibiting the upstream activation of the ubiquitin-proteasome pathway[3].
In vitro, pretreatment of dendritic cells with PYR-41 (5μM) for 30min significantly reduced the increase in cytokine levels of IL-12, TNF-α, and IL-6 induced by angiotensin II[4]. Treatment of MCF-7 breast cancer cells with PYR-41 (1μM) inhibited the rapid increase in AKT and p38/MAPK phosphorylation induced by 17β-estradiol (E2), and suppressed the proliferative effect of E2 on MCF-7 cell colony formation[5].
In vivo, intravenous administration of PYR-41 (5mg/kg) to septic mice significantly improved 10-day survival rate (from 42% to 83%), significantly reduced serum levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and organ damage markers (AST, ALT, and LDH), and significantly improved lung morphology, reduced myeloperoxidase activity, apoptosis, and caspase-3 activation in lung tissue[6]. Intraperitoneal administration of PYR-41 (5, 10mg/kg) to mice with angiotensin II-induced cardiac remodeling reduced angiotensin II-induced hypertension, cardiac hypertrophy, fibrosis, oxidative stress, and inflammation in a dose-dependent manner, and improved cardiac function[7].
References:
[1] Yang Y, Kitagaki J, Dai R M, et al. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics[J]. Cancer research, 2007, 67(19): 9472-9481.
[2] Yoshida K, Kang W, Nakamura A, et al. Ubiquitin-activating enzyme E1 inhibitor PYR-41 retards sperm enlargement after fusion to the egg[J]. Reproductive Toxicology, 2018, 76: 71-77.
[3] Ungermannova D, Parker S J, Nasveschuk C G, et al. Identification and mechanistic studies of a novel ubiquitin E1 inhibitor[J]. Journal of biomolecular screening, 2012, 17(4): 421-434.
[4] Chen C, Meng Y, Wang L, et al. Ubiquitin‐activating enzyme E 1 inhibitor PYR 41 attenuates angiotensin II‐induced activation of dendritic cells via the Iκ B a/NF‐κ B and MKP 1/ERK/STAT 1 pathways[J]. Immunology, 2014, 142(2): 307-319.
[5] Pesiri V, Totta P, Marino M, et al. Ubiquitin‐activating enzyme is necessary for 17β‐estradiol‐induced breast cancer cell proliferation and migration[J]. Iubmb Life, 2014, 66(8): 578-585.
[6] Matsuo S, Sharma A, Wang P, et al. PYR-41, a ubiquitin-activating enzyme E1 inhibitor, attenuates lung injury in sepsis[J]. Shock, 2018, 49(4): 442-450.
[7] Shu Q, Lai S, Wang X M, et al. Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice[J]. Biochemical and Biophysical Research Communications, 2018, 505(1): 317-324.
PYR-41是一种不可逆的、细胞渗透性的泛素激活酶E1抑制剂，IC50值小于10μM，对E2和E3基本无作用[1, 2]。PYR-41通过选择性且不可逆地结合E1的半胱氨酸残基，有效阻断泛素与E1的形成硫酯键，从而抑制整个泛素-蛋白酶体通路的上游活化过程[3]。
在体外，PYR-41（5μM）预处理树突细胞30min，显著降低了血管紧张素II（Angiotensin II）诱导的细胞因子IL-12、TNF-α和IL-6水平的升高[4]。PYR-41（1μM）处理乳腺癌MCF-7细胞，抑制了17β-雌二醇（E2）诱导的AKT和p38/MAPK磷酸化的快速增加，抑制了E2对MCF-7细胞集落数量的增殖作用[5]。
在体内，PYR-41（5mg/kg）通过静脉注射治疗败血症小鼠，显著提高了败血症小鼠的10天存活率（从42%提高到83%），显著降低了血清中促炎细胞因子（TNF-α、IL-1β和IL-6）以及器官损伤标志物（AST、ALT和LDH）的水平，显著改善了小鼠的肺组织形态，降低了肺组织中髓过氧化物酶活性、细胞凋亡数量和caspase-3的激活水平[6]。PYR-41（5、10mg/kg）通过腹腔注射治疗Angiotensin II诱导的心脏重塑模型小鼠，剂量依赖性地降低了Angiotensin II诱导的血压升高、心脏肥大、纤维化、氧化应激和炎症，并改善了心脏收缩功能[7]。