Curaxins: Lead Drugs and Target Discovery in the African Trypanosome

描述（由申请人提供）：布法罗生物实验室公司合成了一系列新型抗锥虫化合物，对全细胞具有纳摩尔活性。口服给药后，Curaxin药物在小鼠血液中达到数十微摩尔浓度，超过杀死培养物中所有血流布氏锥虫所需量的300倍。因此，这些新的药物治疗T。感染布鲁氏菌的老鼠数量巨大。因此，我们将测试三种铅Curaxins治疗T的能力。布鲁氏菌感染的小鼠，使用急性形式和慢性阶段人类非洲锥虫病（HAT）的模型。在非洲锥虫中结合Curaxins的蛋白质尚未鉴定。为了进一步了解Curaxins如何杀死T。布氏杆菌，并准备通过配体辅助药物设计的进一步优化的Curaxin支架的阶段，我们将集中Curaxin结合蛋白的亲和层析和鉴定它们的发现质谱。最后，将通过确定药物对锥虫的Curaxin结合蛋白的生物化学活性的影响来鉴定Curaxin的生物学相关靶标。 公共卫生相关性：需要新的药物来治疗人类非洲锥虫病。本提案中描述的研究评估了使用Curaxins（口服生物可利用药物）治疗HAT小鼠模型的可能性。还尝试鉴定Curaxins的靶标，其在纳摩尔浓度下对培养的血流T有效。布鲁塞。

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.