Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Department of Medicine, University of Vermont, Larner College of Medicine, Burlington, VT 05401, USA.
Sci Transl Med. 2024 Oct 23;16(770):eadm8631. doi: 10.1126/scitranslmed.adm8631.
Cryptosporidiosis is a diarrheal disease caused by infection with 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.
隐孢子虫病是一种由 spp.寄生虫感染引起的腹泻病，是全球营养不良儿童死亡的主要原因。唯一批准的治疗药物硝唑尼特在这一高危患者群体中的疗效有限。迫切需要额外的安全治疗药物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了解，抗隐孢子虫药物的开发受到了阻碍。为了弥补这一知识空白，我们对一组多样化的强效赖氨酸 tRNA 合成酶抑制剂进行了分析，以确定在慢性感染小鼠模型中具有疗效所需的最佳理化和药代动力学特性。这项全面研究的结果说明了在体内实现疗效时平衡溶解度和通透性的重要性。我们的研究结果建立了预测化合物体内疗效的体外溶解度和通透性标准，为指导抗隐孢子虫药物的优化提供了依据。从两个化学结构截然不同的系列中发现了两种化合物（DDD489 和 DDD508），它们具有优异的疗效，被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一种与疾病相关的小牛感染模型中均能显著减少寄生虫。基于这些有希望的数据，这些化合物已被选中进行临床前安全性研究，为这一被忽视的传染病的潜在治疗方法提供了更多选择。
