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一个药物重定向屏幕,用于鞭毛虫,由比较基因组学提供信息

Avril Coghlan¹, Frederick A Partridge^2,3, María Adelaida Duque-Correa¹

¹Wellcome Sanger Institute, Cambridge, United Kingdom.

PLoS neglected tropical diseases

|September 5, 2023

概括

药物重定向显示出治疗鞭虫感染的前景. 虽然许多已批准的药物向虫蛋白质,但体内疗效仍然是一个挑战,因为药物的特性和药理动力学.

科学领域:

寄生虫学的寄生虫学
药物发现药物发现药物发现
传染性疾病传染性疾病

背景情况:

全球有数以亿计的人患有鞭虫 (Trichuris trichiura) 感染.
像阿尔本达这样的当前治疗方法的疗效有限,需要新的治疗策略.

研究的目的:

研究将现有已批准的人类药物改用为新型抗鞭虫剂的潜力.
为了识别针对寄生虫虫蛋白的化合物,用于鞭虫治疗.

主要方法:

对比基因组学确定了409种已批准的药物,预计将向寄生虫虫蛋白质.
活体查评估了在这些药物的存在下成年Trichuris muris (小鼠鞭虫) 的运动性.
有前途的化合物在小鼠模型中进一步进行了体内评估.

主要成果:

14种化合物证明了对T. muris的活体疗效 (EC50 ≤50微米).
在体内对9种选定的化合物的试验结果显示,虫负担的最大减少仅为19%.
高的ex vivo疗效与低的体内结果形成对比,表明药物特性和药理动力学存在挑战.

结论:

该研究成功确定了针对鞭虫蛋白质的批准药物,验证了基因组学方法.
主体的药物吸收和虫的有限吸收阻碍了体内疗效.
未来的发展需要确定药物类似物,减少宿主吸收和增强虫吸收,以有效治疗鞭虫.

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