A drug repurposing screen for whipworms informed by comparative genomics.
A drug repurposing screen for whipworms informed by comparative genomics.
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DOI：
10.1371/journal.pntd.0011205
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发表时间：
2023-09
影响因子：
3.8
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中科院分区：
文献类型：
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全世界有数亿人感染鞭虫鞭虫。由于目前的药物，如阿苯达唑，疗效相对较低，迫切需要新的治疗方法。我们已经调查了批准用于其他人类疾病的药物是否可以被重新用于新型抗鞭虫药物。在之前的比较基因组学分析中，我们确定了409种被批准用于人类的药物，我们预测这些药物将针对寄生虫蛋白。在这里，我们通过评估鞭虫成虫的运动性来测试这些体外实验，鞭虫是一种小鼠鞭虫，是人类鞭虫研究的既定模型。我们在体外鉴定了14个化合物，其EC50值为≤50μM，并选择了9个化合物进行体内试验。然而，在老鼠身上看到的最好的蠕虫负担减少只有19%。对T.Muris的大量体外命中表明，我们成功地预测了可以被批准的药物靶向的寄生虫蛋白。相比之下，这些化合物在小鼠身上的低疗效表明，由于它们的化学性质(如脂溶性、极性、分子量)和药代动力学(如吸收、分布、代谢和排泄)可能(I)促进宿主胃肠道的吸收，从而降低对大肠内蠕虫的利用度，和/或(Ii)限制蠕虫对药物的摄取，这些化合物提出了挑战。这表明，识别减少宿主吸收而增加蠕虫吸收的结构类似物，对于成功开发针对鞭虫的药物可能是必要的。我们的研究描述了一种针对鞭虫的药物再利用筛选，鞭虫导致被忽视的热带疾病鞭虫病。尽管迫切需要更有效的药物来治疗鞭虫感染，但鞭虫一直是极少数药物筛选的重点。结合比较基因组学，以及CHEMBL数据库中药物及其靶点的数据，我们预测了409种被批准用于人类的药物将针对鞭虫蛋白。使用高通量筛选平台，我们然后在体外筛选了这409种抗鞭虫成虫的药物。我们12%的高命中率证明了我们的比较基因组学方法在预测被批准的药物靶向的蠕虫蛋白方面的实用性。我们随后在感染鞭毛虫的小鼠身上测试了最有效的化合物，但在体内没有显著的打击。有趣的是，这与之前发表的针对鞭虫的筛查结果一致，该筛查也报告了有希望的体外命中，但在小鼠中的活性较低。我们讨论了这一发现的可能原因，以及优化未来抗鞭毛虫药物筛选的重要意义。
Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of ≤50 μM against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug development against whipworms. Our study describes a drug repurposing screen against the whipworm Trichuris, which causes the neglected tropical disease trichuriasis. Despite the pressing need for more effective drugs to treat whipworm infections, Trichuris has been the focus of extremely few drug screens. Using a combination of comparative genomics, and data on drugs and their targets from the ChEMBL database, we predicted that 409 drugs approved for human use would target Trichuris proteins. Using a high-throughput screening platform, we then screened these 409 drugs against Trichuris adults ex vivo. Our high hit rate of 12% demonstrated the utility of our comparative genomics approach to predict worm proteins for targeting by approved drugs. We subsequently tested the most active compounds in Trichuris-infected mice, but there were no significant hits in vivo. Interestingly, this accorded with a previously published screen against Trichuris, which also reported promising ex vivo hits but low activity in mice. We discuss possible reasons for this finding, and important implications for optimising future drug screens against Trichuris.
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影响因子：
3.8
作者：
Buckingham SD;Partridge FA;Poulton BC;Miller BS;McKendry RA;Lycett GJ;Sattelle DB
通讯作者：
Sattelle DB
DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
影响因子：
3.2
作者：
Keiser J;Panic G;Adelfio R;Cowan N;Vargas M;Scandale I
通讯作者：
Scandale I
影响因子：
4.6
作者：
Dong C;Yang R;Li H;Ke K;Luo C;Yang F;Shi XN;Zhu Y;Liu X;Wong MH;Lin G;Wang X;Leung KS;Kung HF;Chen C;Lin MC
通讯作者：
Lin MC
影响因子：
2
作者：
Cowan, Noemi;Raimondo, Alessia;Keiser, Jennifer
通讯作者：
Keiser, Jennifer