Brequinar is a specific inhibitor of dihydroorotate dehydrogenase DHODH, with an IC50 value of approximately 20nM in vitro [1]. DHODH is an enzyme in the de novo pyrimidine biosynthesis pathway. Buquina's mechanism of action is to target viral DNA synthesis by inhibiting DHODH activity and depleting the cellular pyrimidine pool [2].
In vitro, Buquina (0-75μM) treated BSC-40 cells infected with CTGV virus for 24 hours, significantly inhibiting the intracellular CTGV virus production in a dose-dependent manner, with an EC50 of 0.017±0.05μM, and could be inhibited at a high concentration of 75μM. Ensure that cell viability is maintained at nearly 80%[2]. Buquina (0-25μM) treated Vero cells infected with DENV-2, WNV, YFV, PWV, and WEEV viruses for 42 hours, effectively inhibiting all tested viruses, and the antiviral activity was not caused by compound-mediated toxicity [3]. Buquinar (0-100 μM) treated IBRS-2 cells infected with FMDV for 8 hours and effectively inhibited the protein and mRNA expression of FMDV [4].
In vivo, Buquina (50μg) treated FMDV-infected suckling mice (body weight 3-4g) through intraperitoneal injection, significantly prolonging the survival time of suckling mice and reducing the lesions of cardiac tissue [4]. Buquina (10-20 mg/kg) was treated with BALB/c mice through intraperitoneal injection, causing a 31% reduction in blood cell accumulation volume percentage, and a 30% and 25% reduction in UTP and CTP levels in bone marrow cells, respectively, indicating that Buquina Quinal treatment of mice may induce anemia [5].
References:
[1] Sykes D B , Kfoury Y S , Mercier F ,et al.Inhibition of the Enzyme Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia[J].Blood, 2016, 128(22):1656-1656.
[2] Schnellrath L C , Damaso C R .Potent antiviral activity of brequinar against the emerging Cantagalo virus in cell culture[J].International journal of antimicrobial agents, 2011, 38(5):435-441.
[3] Qing M , Zou G , Wang Q Y ,et al.Characterization of dengue virus resistance to brequinar in cell culture.[J].Antimicrobial Agents and Chemotherapy, 2010, 54(9):3686-3695.
[4] Li S F , Gong M J , Sun Y F ,et al.Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo[J].Biomedicine & pharmacotherapy, 2019, 116:108982.
[5] Xu X , Williams J W , Shen J ,et al.In vitro and in vivo mechanisms of action of the antiproliferative and immunosuppressive agent, brequinar sodium.[J].Journal of Immunology, 1998, 160(2):846-53.
布喹那（Brequinar）是一种特异性的二氢乳清酸脱氢酶DHODH抑制剂，在体外IC50值约为20nM[1]。DHODH是嘧啶从头生物合成途径的一种酶，布喹那的作用机制是通过抑制DHODH活性，耗尽细胞嘧啶池来靶向病毒DNA合成[2]。
在体外，布喹那（0-75μM）处理受CTGV病毒感染的BSC-40细胞24h，以剂量依赖性方式显著抑制胞内CTGV病毒产量，EC50为0.017±0.05μM，且在高浓度75μM时能保证细胞活力保持在近80%[2]。布喹那（0-25μM）分别处理受DENV-2, WNV, YFV, PWV, WEEV病毒感染的Vero细胞42h，有效抑制所有测试的病毒，且抗病毒活性并非由化合物介导的毒性引起[3]。布喹那（0-100μM）处理感染FMDV的IBRS-2细胞8h，有效抑制FMDV的蛋白和mRNA表达[4]。
在体内，布喹那（50μg）通过腹腔注射治疗受FMDV感染的乳鼠（体重3-4g），显著延长了乳鼠的存活时间，减轻了心脏组织的病变[4]。布喹那（10-20 mg/kg）通过腹腔注射处理BALB/c小鼠，引起血细胞堆积体积百分比减少了31%，骨髓细胞中的UTP和CTP水平分别降低了30%和 25%，说明布喹那治疗小鼠可能会诱发贫血[5]。