Curaxins: Lead Drugs and Target Discovery in the African Trypanosome

描述(申请人提供)：Buffalo BioLabs Inc.合成了一系列新型抗锥虫化合物，具有对整个细胞的纳摩尔活性。在小鼠口服药物后，Curaxin药物在小鼠血液中的微摩尔浓度达到数十微摩尔，超过了在培养条件下杀死所有血液中布鲁氏锥虫所需的量的300倍。因此，这些新药治愈感染布氏毛滴虫的小鼠的潜力是巨大的。因此，我们将使用急性期和慢性期人类非洲锥虫病(HAT)模型来测试三种库拉辛铅治疗布氏锥虫感染小鼠的能力。非洲锥虫体中与库拉辛结合的蛋白质尚未确定。为了进一步了解Curaxin是如何杀死布氏毛滴虫的，并为通过配基辅助药物设计进一步优化Curaxin支架做准备，我们将通过亲和层析浓缩Curaxin结合蛋白，并通过发现质谱学对其进行鉴定。最后，库拉辛的生物相关靶点(S)将通过测定药物对锥虫体内库拉辛结合蛋白的生化活性的影响来确定。 公共卫生相关性：需要新药来治疗人类非洲锥虫病。这项建议中描述的研究评估了使用Curaxin的可能性，Curaxin是口服生物利用药，用于治疗HAT的小鼠模型。还试图确定Curaxin的靶标，它在纳摩尔浓度下对培养的布鲁氏毛滴虫有效。

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.