High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.
High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.
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DOI：
10.1038/srep13891
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发表时间：
2015-09-25
影响因子：
4.6
通讯作者：
Thomas CJ
中科院分区：
文献类型：
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作者：
Mott BT;Eastman RT;Guha R;Sherlach KS;Siriwardana A;Shinn P;McKnight C;Michael S;Lacerda-Queiroz N;Patel PR;Khine P;Sun H;Kasbekar M;Aghdam N;Fontaine SD;Liu D;Mierzwa T;Mathews-Griner LA;Ferrer M;Renslo AR;Inglese J;Yuan J;Roepe PD;Su XZ;Thomas CJ
疟原虫的抗药性是一个持续的威胁。必须以更快的速度确定新的治疗方法，特别是新的药物组合。为了应对对新的抗疟疾药物组合的迫切需求，我们筛选了大量批准和研究的药物，测试了13,910对药物，并确定了许多有希望的抗疟疾药物组合。已知的抗疟疾药物方案的活性得到证实，并发现了无数种新的正相互作用的药物配对。网络和聚类分析加强了已建立的已知药物组合的机制关系，并确定了几个新的机制假说。从每种寄生虫菌株4,600个组合的11个筛选中，我们进一步研究了已批准的抗疟药、钙稳态调节剂和磷脂酰肌醇3-激酶抑制剂(PI3K)与哺乳动物靶标雷帕霉素(MTOR)之间的相互作用。这些研究突出了重要的靶点和途径，并为临床可操作的抗疟疾治疗提供了有希望的线索。
Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy.