Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.,Nature Communications

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Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.
Nature Communications ( IF 14.7 ) Pub Date : 2019-06-27 , DOI: 10.1038/s41467-019-10687-y
Christopher S Lunde ₁ , Erin E Stebbins ₂ , Rajiv S Jumani _{2,

3} , Md Mahmudul Hasan _{2,

3} , Peter Miller ₂ , John Barlow ₄ , Yvonne R Freund ₁ , Pamela Berry ₁ , Rianna Stefanakis ₁ , Jiri Gut ₅ , Philip J Rosenthal ₅ , Melissa S Love ₆ , Case W McNamara ₆ , Eric Easom ₁ , Jacob J Plattner ₁ , Robert T Jacobs ₁ , Christopher D Huston _{2,

3}

Affiliation

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

中文翻译：

鉴定用于治疗隐孢子虫病的有效苯并氧杂硼罗候选药物。

隐孢子虫病是导致幼儿危及生命的腹泻的主要原因，并导致艾滋病患者慢性腹泻，但唯一批准的治疗方法对营养不良的儿童和免疫功能低下的人无效。我们在这里使用药物重新定位策略并确定了一种有前途的抗隐孢子虫候选药物。筛选由四种抗原虫化学支架类似物组成的苯并氧杂硼化合物文库，用于隐孢子虫生长抑制剂的被忽视的热带疾病的临床前开发，鉴定出 6-甲酰胺苯并氧硼杂硼烷 AN7973。 AN7973 阻断细胞内寄生虫的发育，似乎具有杀寄生虫作用，并有效抑制与人类健康最相关的两种隐孢子虫：小隐孢子虫和人隐孢子虫。它在急性和既定感染的小鼠模型以及隐孢子虫病的新生奶牛模型中均有效。 AN7973还具有良好的安全性、稳定性和PK参数，因此是治疗隐孢子虫病的令人兴奋的候选药物。

更新日期：2019-06-27

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