Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.

中文翻译：

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隐孢子虫赖氨酰-tRNA 合成酶抑制剂定义了实现疗效所需的溶解度和渗透性之间的相互作用


隐孢子虫病是一种由隐孢子虫属寄生虫感染引起的腹泻病，是全世界营养不良儿童死亡的主要原因。唯一获批的治疗方法硝唑尼特对这一高危患者群体的疗效有限。迫切需要额外的安全疗法来解决这一未满足的医疗需求。然而，由于缺乏对治疗这种胃肠道感染所需的最佳化合物特性的理解，抗隐孢子虫药物的开发受到阻碍。为了解决这一知识差距，分析了一组不同的有效赖氨酰-tRNA 合成酶抑制剂，以确定在慢性小鼠感染模型中疗效所需的最佳物理化学和药代动力学特性。这项综合研究的结果说明了平衡溶解度和渗透性以达到体内疗效的重要性。我们的结果建立了溶解度和渗透性的体外标准，这些标准可以预测化合物在体内的疗效，以指导抗隐孢子虫药物的优化。来自化学不同系列的两种化合物 （DDD489 和 DDD508） 被确定为表现出卓越的疗效，并优先进行进一步评估。这两种化合物在免疫功能低下的小鼠模型和疾病相关的小牛感染模型中都实现了显著的寄生虫减少。基于这些有希望的数据，这些化合物已被选择进行临床前安全性研究，扩大了这种被忽视的传染病的潜在治疗组合。