The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing.
The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing.
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DOI：
10.1371/journal.pntd.0001297
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发表时间：
2011-08
影响因子：
3.8
通讯作者：
Pollastri MP
中科院分区：
文献类型：
--
作者：
Diaz-Gonzalez R;Kuhlmann FM;Galan-Rodriguez C;Madeira da Silva L;Saldivia M;Karver CE;Rodriguez A;Beverley SM;Navarro M;Pollastri MP
靶再利用利用在一个生物体中获得的“可药物”靶标的知识，并利用这些信息在其他生物体中寻找新的潜在药物靶点。在这里，我们描述了这样的研究，以评估针对哺乳动物雷帕霉素靶标(MTOR)和人磷脂酰肌醇-3-激酶(PI3Ks)的激酶结构域的抑制剂是否对动体寄生虫布氏锥虫、克鲁兹锥虫、大利什曼原虫和杜诺瓦尼锥虫显示出希望。锥虫基因组编码至少12种属于PI3K蛋白超家族的蛋白质，其中一些是寄生虫所特有的。此外，共享的PI3K在序列上与人类宿主的PI3K有很大的不同，从而为选择性抑制提供了机会。我们重点研究了8种针对mTOR和/或PI3K的抑制剂，这些抑制剂来自临床前和临床开发的不同阶段，并针对体外寄生虫培养和体内感染模型进行了测试。几种抑制剂在培养中对这些微生物表现出微摩尔或更好的效果。一种名为NVP-BEZ235的化合物显示出亚纳摩尔效力，对培养的寄生虫有疗效，并能够在罗德赛毛滴虫感染的动物模型中清除寄生虫血症。这些研究有力地表明，哺乳动物的PI3/TOR激酶抑制剂是抗锥虫药物开发的有效起点。我们的数据表明，NVP-BEZ235是一种治疗实体瘤的高级临床候选药物，作为治疗非洲昏睡病的药物值得进一步研究。在我们的研究中，我们描述了已建立的磷脂酰肌醇-3-激酶(PI3K)和哺乳动物靶标雷帕霉素(MTOR)激酶抑制剂对三种锥虫寄生虫的效力：布鲁氏锥虫、克鲁兹锥虫和利什曼原虫，这三种寄生虫分别是非洲昏睡病、恰加斯病和利什曼病的病原体。我们注意到，这些寄生虫和人类表达类似的激酶酶。由于这些类似的人类靶点多年来一直被制药行业用于发现细胞生长和增殖抑制剂，因此作为人类抗癌剂开发的化合物也应该具有抑制寄生虫生长和增殖的作用。考虑到这一点，我们选择了8种已建立的PI3K和mTOR抑制剂来分析这些病原体。在这些抑制剂中，有一种是抗癌的高级临床候选药物NVP-BEZ235，我们在寄生虫培养和布氏毛滴虫感染的小鼠模型中证明了它是一种高效的胰酶抑制剂。此外，我们还描述了这些抑制剂对寄生虫生长和其他细胞特征的影响的观察。
Target repurposing utilizes knowledge of “druggable” targets obtained in one organism and exploits this information to pursue new potential drug targets in other organisms. Here we describe such studies to evaluate whether inhibitors targeting the kinase domain of the mammalian Target of Rapamycin (mTOR) and human phosphoinositide-3-kinases (PI3Ks) show promise against the kinetoplastid parasites Trypanosoma brucei, T. cruzi, Leishmania major, and L. donovani. The genomes of trypanosomatids encode at least 12 proteins belonging to the PI3K protein superfamily, some of which are unique to parasites. Moreover, the shared PI3Ks differ greatly in sequence from those of the human host, thereby providing opportunities for selective inhibition. We focused on 8 inhibitors targeting mTOR and/or PI3Ks selected from various stages of pre-clinical and clinical development, and tested them against in vitro parasite cultures and in vivo models of infection. Several inhibitors showed micromolar or better efficacy against these organisms in culture. One compound, NVP-BEZ235, displayed sub-nanomolar potency, efficacy against cultured parasites, and an ability to clear parasitemia in an animal model of T. brucei rhodesiense infection. These studies strongly suggest that mammalian PI3/TOR kinase inhibitors are a productive starting point for anti-trypanosomal drug discovery. Our data suggest that NVP-BEZ235, an advanced clinical candidate against solid tumors, merits further investigation as an agent for treating African sleeping sickness. In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics.
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影响因子：
11.4
作者：
Brunn, GJ;Williams, J;Abraham, RT
通讯作者：
Abraham, RT
影响因子：
4
作者：
Andrews, KT;Walduck, A;Parsons, PG
通讯作者：
Parsons, PG
DOI：
10.1126/science.1169464
发表时间：
2009-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Akopyants NS;Kimblin N;Secundino N;Patrick R;Peters N;Lawyer P;Dobson DE;Beverley SM;Sacks DL
通讯作者：
Sacks DL
影响因子：
4.8
作者：
Ballou, Lisa M.;Selinger, Elzbieta S.;Lin, Richard Z.
通讯作者：
Lin, Richard Z.
影响因子：
50.3
作者：
Fan, Qi-Wen;Knight, Zachary A.;Weiss, William A.
通讯作者：
Weiss, William A.