Antileishmanial activity of the terpene nerolidol
Antileishmanial activity of the terpene nerolidol
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DOI：
10.1128/aac.49.5.1679-1687.2005
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发表时间：
2005-05-01
影响因子：
4.9
通讯作者：
Uliana, SRB
中科院分区：
文献类型：
--
作者：
Arruda, DC;D'Alexandri, FL;Uliana, SRB
橙花叔醇是一种用作食品调味剂的倍半萜，目前正在测试中，作为治疗药物经皮给药的皮肤渗透促进剂，评价橙花叔醇对利什曼原虫属的活性。橙花叔醇对亚马逊利什曼原虫L. braziliensis和L. chagasi promastigotes和L.亚马逊无鞭毛体的体外50%抑制浓度分别为85、74、75和67 μ M。对L.用100 μ M橙花叔醇处理亚马逊河原虫感染的巨噬细胞导致感染率降低95%。在橙花醇处理的前鞭毛体中观察到类异戊二烯生物合成的抑制，如通过[2-C-14]甲羟戊酸（MVA）或[1-C-14]乙酸前体掺入长萜醇、麦角甾醇和泛醌的减少所示。这种药物作用可归因于甲羟戊酸途径中早期步骤的阻断，因为聚类异戊二烯中前体[1（n）H-3]法呢基焦磷酸的掺入不受橙花叔醇抑制。L.用100 mg/kg/天的腹膜内剂量治疗亚马逊河原虫感染的BALB/c小鼠12天，或用5或10%的软膏局部治疗4周。对于两种处理途径，均观察到橙花叔醇处理的小鼠中的病变尺寸显著减小。然而，长期随访表明，在这种高度易感的动物模型中，该疾病并未治愈。尽管如此，橙花叔醇对这些寄生虫的体外活性可能被证明是开发治疗利什曼病新药的有用工具。此外，在利什曼原虫中发现了具有11和12个异戊二烯单元的多萜醇的生物合成，正如对其他锥虫和顶复门所描述的那样。
The activity of nerolidol, a sesquiterpene used as a food-flavoring agent and currently under testing as a skin penetration enhancer for the transdermal delivery of therapeutic drugs, was evaluated against Leishmania species. Nerolidol inhibited the growth of Leishmania amazonensis, L. braziliensis, and L. chagasi promastigotes and L. amazonensis amastigotes with in vitro 50% inhibitory concentrations of 85, 74, 75, and 67 p,M, respectively. The treatment of L. amazonensis-infected macrophages with 100 mu M nerolidol resulted in 95% reduction in infection rates. Inhibition of isoprenoid biosynthesis, as shown by reduced incorporation of [2-C-14]mevalonic acid (MVA) or [1-C-14]acetic acid precursors into dolichol, ergosterol, and ubiquinone, was observed in nerolidol-treated promastigotes. This drug effect can be attributed to the blockage of an early step in the mevalonate pathway, since incorporation of the precursor [1(n)H-3]farnesyl pyrophosphate in polyisoprenoids is not inhibited by nerolidol. L. amazonensis-infected BALB/c mice were treated with intraperitoneal doses of 100 mg/kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. Significant reduction of lesion sizes in nerolidol treated mice was observed for both treatment routes. However, long-term follow up indicated that the disease was not cured in this highly susceptible animal model. Nonetheless, the in vitro activity of nerolidol against these parasites may prove a useful tool for the development of new drugs for the treatment of leishmaniasis. In addition, biosynthesis of dolichols with 11 and 12 isoprene units was identified in Leishmania, as described for other trypanosomatids and Apicomplexa.