A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.
A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.
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DOI：
10.1128/aac.01505-17
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发表时间：
2018-04
影响因子：
4.9
通讯作者：
Huston CD
中科院分区：
文献类型：
--
作者：
Jumani RS;Bessoff K;Love MS;Miller P;Stebbins EE;Teixeira JE;Campbell MA;Meyers MJ;Zambriski JA;Nunez V;Woods AK;McNamara CW;Huston CD
隐孢子虫病会导致5岁以下儿童出现危及生命的腹泻，以及免疫缺陷人群（尤其是艾滋病患者）出现长期腹泻。标准治疗药物硝唑尼特对儿童有一定疗效，但对免疫功能低下者无效。除了需要新药外，还需要更好地了解驱动体内疗效的药物特性，以促进药物研发。我们报道了一种用于隐孢子虫药物研发的基于哌嗪的先导化合物MMV665917的鉴定，以及一种用于其特性描述的新药效学方法。从疟疾药物研发公司疟疾药盒中鉴定出MMV665917之后，进行了剂量 - 反应研究、体外毒性研究以及使用市售类似物的构效关系研究。该化合物对微小隐孢子虫爱荷华株和现场分离株的效力与对人隐孢子虫的效力相当。此外，与硝唑尼特、氯法齐明和巴龙霉素不同，MMV665917在慢性隐孢子虫病的非肥胖型糖尿病重症联合免疫缺陷γ小鼠模型中似乎具有治愈作用。MMV665917在急性隐孢子虫病的γ干扰素基因敲除小鼠模型中也有效。为了确定在这种慢性感染小鼠模型中的疗效是否可能与化合物对微小隐孢子虫是具有杀寄生虫作用还是抑制寄生虫作用有关，我们开发了一种新的体外寄生虫持续存在测定法。该测定法表明MMV665917具有杀寄生虫作用，这与硝唑尼特、氯法齐明和巴龙霉素不同。该测定法还能够确定使寄生虫消除速率最大化所需的化合物浓度。这种时间 - 杀灭测定法可用于对隐孢子虫早期药物先导物进行优先级排序，并可能有助于规划体内疗效实验。总之，这些结果确定MMV665917是一种有前景的先导化合物，并建立了一种表征潜在抗隐孢子虫药物的新方法。
Cryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies, in vitro toxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound against Cryptosporidium parvum Iowa and field isolates was comparable to that against Cryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic for C. parvum, we developed a novel in vitro parasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stage Cryptosporidium drug leads and may aid in planning in vivo efficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.