Zaragozic Acid A is a competitive inhibitor of squalene synthase, with a Ki value of 78pM [1]. Zaragozic Acid A inhibits hepatic cholesterol synthesis, with an IC50 value of 6μM[2]. Zaragozic Acid A impairs staphyloxanthin formation and is a potent biofilm inhibitor in S. aureus and Bacillus subtilis by targeting CrtM enzyme without causing cell death[3]. Zaragozic Acid A has been widely used to regulate the cholesterol levels within cells and to inhibit the transformation of bronchial fibroblasts into myofibroblasts[4].
In vitro, Zaragozic Acid A treatment (100μM) for 72 hours significantly reduced the cholesterol level and increased the dolichol (Dol)-P-Man levels in human primary skin fibroblasts (HPSFs) with congenital disorders of glycosylation (CDG)[5]. Treatment with 10μg/ml Zaragozic Acid A for 48 hours would impair the maintenance of the Tat2p protein and the absorption of tryptophan in the tryptophan auxotrophic (trp1) yeast cells[6]. Treatment with 10μM Zaragozic Acid A for 48 hours significantly inhibited the replication of live Dengue virus type 2 (DEN-2 NGC) in K562 cells, with an EC50 value of 8.3μM[7].
In vivo, Zaragozic acid A treatment (3mg/kg/day; s.c.) caused massive production of Farnesol-derived dicarboxylic acids in urine of female Swiss Webster mice [8].
References:
[1] Bergstrom J D, Kurtz M M, Rew D J, et al. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase[J]. Proceedings of the National Academy of Sciences, 1993, 90(1): 80-84.
[2] Ponpipom M M, Girotra N N, Bugianesi R L, et al. Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives[J]. Journal of medicinal chemistry, 1994, 37(23): 4031-4051.
[3] Liu C I, Jeng W Y, Chang W J, et al. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase[J]. Journal of Biological Chemistry, 2012, 287(22): 18750-18757.
[4] Michalik M, Soczek E, Kosińska M, et al. Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients[J]. European Journal of Pharmacology, 2013, 704(1-3): 23-32.
[5] Haeuptle M A, Welti M, Troxler H, et al. Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor zaragozic acid[J]. Journal of Biological Chemistry, 2011, 286(8): 6085-6091.
[6] Daicho K, Maruyama H, Suzuki A, et al. The ergosterol biosynthesis inhibitor zaragozic acid promotes vacuolar degradation of the tryptophan permease Tat2p in yeast[J]. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2007, 1768(7): 1681-1690.
[7] Rothwell C, LeBreton A, Ng C Y, et al. Cholesterol biosynthesis modulation regulates dengue viral replication[J]. Virology, 2009, 389(1-2): 8-19.
[8] Vaidya S, Bostedor R, Kurtz M M, et al. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A[J]. Archives of biochemistry and biophysics, 1998, 355(1): 84-92.
Zaragozic Acid A是角鲨烯合酶的竞争性抑制剂，Ki值为78pM[1]。Zaragozic Acid A可抑制肝脏胆固醇合成，IC50值为6μM[2]。Zaragozic Acid A能阻碍葡萄球菌黄素的形成，并通过靶向CrtM酶在不引起细胞死亡的情况下，成为金黄色葡萄球菌和枯草芽孢杆菌的有效生物膜抑制剂[3]。Zaragozic Acid A已广泛用于调节细胞内胆固醇水平，并抑制支气管成纤维细胞向肌成纤维细胞转化[4]。
在体外，Zaragozic Acid A处理（100μM）72小时显著降低了患有先天性糖基化障碍（CDG）的人原代皮肤成纤维细胞（HPSFs）中的胆固醇水平，并增加了dolichol (Dol)-P-Man的水平[5]。用10μg/ml的Zaragozic Acid A处理48小时会损害色氨酸营养缺陷型（trp1）酵母细胞中Tat2p蛋白的维持和色氨酸的吸收[6]。用10μM的Zaragozic Acid A处理48小时显著抑制了登革病毒2型（DEN-2 NGC）在K562细胞中的复制，EC50值为8.3μM [7]。
在体内，Zaragozic Acid A处理（3mg/kg/day；皮下注射）导致雌性Swiss Webster小鼠尿液中大量产生法尼醇衍生的二羧酸[8]。