A drug repurposing screen for whipworms informed by comparative genomics
A drug repurposing screen for whipworms informed by comparative genomics
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通过比较基因组学对鞭虫进行药物再利用筛选
DOI：
10.1101/2023.03.02.530747
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Coghlan A
中科院分区：
文献类型：
--
作者：
Coghlan A
全世界有数亿人感染了鞭虫。由于目前的药物如阿苯达唑的疗效相对较低，迫切需要新的治疗方法。我们已经研究了批准用于其他人类疾病的药物是否可以重新用作新的抗鞭虫药物。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，我们预测这些药物可以靶向寄生虫蛋白。在这里，我们通过评估鼠鞭虫（trichuris muris）成虫的运动能力来测试这些性活虫，鼠鞭虫是人类鞭虫研究的一个既定模型。我们鉴定出14个化合物对t的ec50值≤50 μM。6例体外试验，并选择9例体内试验。然而，在小鼠身上看到的最好的蠕虫负荷减少仅为19%。大量的人感染了t病毒。muriss表示，我们成功地预测了可以被批准的药物靶向的寄生虫蛋白质。相比之下，这些化合物在小鼠体内的低功效表明，由于它们的化学性质（如亲脂性、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，从而减少大肠内蠕虫的可利用性，和/或（ii）限制蠕虫的药物摄取。这表明，鉴定减少宿主吸收、增加蠕虫吸收的结构类似物，可能是成功开发抗鞭虫药物的必要条件。
Hundreds of millions of people worldwide are infected with the whipwormTrichuris 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 theseex vivoby assessing motility of adult worms ofTrichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50values of≤50 μM againstT.muris ex vivo, and selected nine for testingin vivo. However, the best worm burden reduction seen in mice was just 19%. The high number ofex vivohits againstT.murisshows 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.
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影响因子：
2.4
作者：
Mendonca-Silva, D. L.;Novozhilova, E.;Day, T. A.
通讯作者：
Day, T. A.
被遗忘的人们
DOI：
--
发表时间：
2017
期刊：
影响因子：
--
作者：
Anne Thiessen
通讯作者：
Anne Thiessen
影响因子：
2
作者：
Cowan, Noemi;Raimondo, Alessia;Keiser, Jennifer
通讯作者：
Keiser, Jennifer
影响因子：
3.3
作者：
Grau-Pujol, Berta;Gandasegui, Javier;Escola, Valdemiro;Marti-Soler, Helena;Cambra-Pelleja, Maria;Demontis, Maria;Brienen, Eric A. T.;Jamine, Jose Carlos;Muchisse, Osvaldo;Cossa, Anelsio;Sacoor, Charfudin;Cano, Jorge;Van Lieshout, Lisette;Martinez-Valladares, Maria;Munoz, Jose
通讯作者：
Munoz, Jose
影响因子：
3.8
作者：
Panic G;Vargas M;Scandale I;Keiser J
通讯作者：
Keiser J