Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.
Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.
复制标题
DOI：
10.1021/acsinfecdis.0c00546
复制
发表时间：
2021-01-08
影响因子：
5.3
通讯作者：
Steel PG
中科院分区：
文献类型：
--
作者：
Mina JGM;Charlton RL;Alpizar-Sosa E;Escrivani DO;Brown C;Alqaisi A;Borsodi MPG;Figueiredo CP;de Lima EV;Dickie EA;Wei W;Coutinho-Silva R;Merritt A;Smith TK;Barrett MP;Rossi-Bergmann B;Denny PW;Steel PG
目前利什曼病的化疗药物存在多种缺陷，需要安全、有效且负担得起的新药物。这项研究描述了一种成功的药物再利用方法，该方法将非处方抗组胺药富马酸氯马斯汀确定为潜在的抗利什曼病候选药物。在对大型利什曼原虫 (Lmj) 前鞭毛体进行二次筛选后，对鞘脂合酶（肌醇磷酸神经酰胺合酶，IPCS）抑制剂的筛选提供了 16 种活性化合物。通过针对 LmjIPCS 和巨噬细胞内 L.major 无鞭毛体的剂量反应进行进一步细化，确定富马酸氯马斯汀对宿主巨噬细胞具有良好的活性和选择性。鞘脂缺陷型 L.major 突变体 (ΔLmjLCB2) 的敏感性降低以及富马酸氯马斯汀治疗后磷脂和鞘脂谱的改变支持了靶向参与。该药物还诱导宿主细胞对感染的增强反应，表明其具有多重药理作用。该活性在一组旧世界和新世界利什曼原虫物种中持续存在，在亚马逊利什曼原虫感染的小鼠模型中表现出与目前使用的药物葡聚糖时间相当的体内活性。总体而言，这些数据验证了 IPCS 作为抗利什曼病药物靶点，并表明富马酸氯马斯汀是重新用于治疗利什曼病的候选药物。
Current chemotherapeutics for leishmaniasis have multiple deficiencies, and there is a need for new safe, efficacious, and affordable medicines. This study describes a successful drug repurposing approach that identifies the over-the-counter antihistamine, clemastine fumarate, as a potential antileishmanial drug candidate. The screening for inhibitors of the sphingolipid synthase (inositol phosphorylceramide synthase, IPCS) afforded, following secondary screening against Leishmania major (Lmj) promastigotes, 16 active compounds. Further refinement through the dose response against LmjIPCS and intramacrophage L. major amastigotes identified clemastine fumarate with good activity and selectivity with respect to the host macrophage. On target engagement was supported by diminished sensitivity in a sphingolipid-deficient L. major mutant (ΔLmjLCB2) and altered phospholipid and sphingolipid profiles upon treatment with clemastine fumarate. The drug also induced an enhanced host cell response to infection indicative of polypharmacology. The activity was sustained across a panel of Old and New World Leishmania species, displaying an in vivo activity equivalent to the currently used drug, glucantime, in a mouse model of L. amazonensis infection. Overall, these data validate IPCS as an antileishmanial drug target and indicate that clemastine fumarate is a candidate for repurposing for the treatment of leishmaniasis.
登录
查看更多内容
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
4.9
作者：
Aeed, Paul A.;Young, Casey L.;Elhammer, Ake P.
通讯作者：
Elhammer, Ake P.
DOI：
10.1590/s0074-02762007000100022
发表时间：
2007-02-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Campbell, David A;Sturm, Nancy R
通讯作者：
Sturm, Nancy R
影响因子：
3.8
作者：
De Rycker, Manu;Thomas, John;Gray, David W.
通讯作者：
Gray, David W.
影响因子：
--
作者：
Costa, Solange dos Santos;Golim, Marjorie de Assis;Giorgio, Selma
通讯作者：
Giorgio, Selma