Curaxins: Lead Drugs and Target Discovery in the African Trypanosome

描述（由申请人提供）：Buffalo BioLabs INC合成了一系列新型抗锥虫化合物，具有抗全细胞的纳摩尔活性。经小鼠口服后，Curaxin药物在小鼠血液中的浓度达到数十微摩尔，超过杀死培养的所有血流中的布鲁氏锥虫所需浓度的300倍。因此，这些新药治愈感染布鲁氏杆菌的小鼠的潜力是巨大的。因此，我们将使用急性和慢性非洲人类锥虫病（HAT）模型来测试三种Curaxins先导药物治疗布鲁氏菌感染小鼠的能力。非洲锥虫中结合Curaxins的蛋白质尚未被确定。为了进一步了解Curaxin如何杀死T. bruei，并为通过配体辅助药物设计进一步优化Curaxin支架准备阶段，我们将通过亲和色谱法浓缩Curaxin结合蛋白，并通过发现质谱法对其进行鉴定。最后，通过确定药物对锥虫中Curaxin结合蛋白的生化活性的影响，确定Curaxin的生物学相关靶点。

DESCRIPTION (provided by applicant): Buffalo BioLabs INC has synthesized a series of novel anti-trypanosome compounds with nanomolar activity against whole cells. After oral administration to mice, the Curaxin drugs reach tens of micromolar concentration in mouse blood, exceeding by 300-fold the amount needed to kill all bloodstream Trypanosoma brucei in culture. Thus the potential for these novel drugs to cure T. brucei-infected mice is immense. Therefore, we will test the ability of three lead Curaxins to cure T. brucei-infected mice, using models of both acute form and chronic stage human African trypanosomiasis (HAT). Proteins that bind Curaxins in the African trypanosome have not been identified. To further our understanding of how Curaxins kill T. brucei, and to prepare the stage for further optimization of the Curaxin scaffold by ligand-assisted drug design, we will concentrate Curaxin- binding proteins by affinity chromatography and identify them by discovery mass-spectrometry. Finally, the biologically relevant target(s) of Curaxin will be identified by determining the effect of the drug on biochemical activities of the Curaxin-binding proteins from the trypanosome. PUBLIC HEALTH RELEVANCE: New drugs are needed for treatment of human African trypanosomiasis. The studies described in this proposal evaluate the possible of using Curaxins, are orally bioavailable drugs, as treatment of HAT in a mouse model of the disease. Attempts are also made to identify the targets of Curaxins, which are effective in nanomolar concentrations against cultured bloodstream T. brucei.