Curaxins: Lead Drugs and Target Discovery in the African Trypanosome

Curaxins：非洲锥虫的先导药物和靶点发现

• 批准号: 8269332
• 负责人: KOJO A. MENSA-WILMOT
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269332
• 关键词: Acute; Adsorption; Affinity; Affinity Chromatography; African; African Trypanosomiasis; Binding Proteins; Bioavailable; Biochemical; Bioinformatics; Blood; Blood Circulation; Buffaloes; Cells; Chemicals; Chronic; Chronic Disease; Development; Disease; Drug Delivery Systems; Drug Design; Drug Kinetics; Escherichia coli; Excretory function; Future; Gel; Human; Lead; Ligands; Mass Spectrum Analysis; Metabolism; Modeling; Mus; Neuraxis; Oral Administration; Peptides; Pharmaceutical Preparations; Phase; Plasma; Protein Binding; Proteins; Recombinant Proteins; Series; Shotguns; Slice; Staging; Testing; Trypanosoma; Trypanosoma brucei brucei; Validation; enzyme activity; genotoxicity; killings; mouse model; novel; polypeptide; scaffold

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.

描述（由申请人提供）：Buffalo Biolabs Inc已合成了一系列新型的抗肌体化合物，具有对全细胞的纳摩尔活性。口服对小鼠进行口服后，库拉辛药物在小鼠血液中达到数十亿个微摩尔浓度，超过了杀死培养物中所有血流锥虫所需的量300倍。因此，这些新型药物可以治愈T. brucei感染的小鼠的潜力是巨大的。因此，我们将使用急性形式和慢性阶段的人类非洲锥虫病（HAT）的模型来测试三种铅curaxins治愈t. brucei感染小鼠的能力。尚未鉴定在非洲锥虫中结合curaxins的蛋白质。为了进一步了解库糖蛋白如何杀死布鲁氏菌，并准备通过配体辅助药物设计进一步优化库拉辛支架的阶段，我们将通过亲和力色谱浓缩curaxin粘合蛋白，并通过发现质谱质谱法识别它们。最后，将通过确定药物对锥虫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：治疗人类非洲锥虫病需要新药。该提案中描述的研究评估了使用curaxins的可能性是口服的可生物利用药物，作为对疾病小鼠模型中HAT的治疗。还试图识别curaxins的靶标，库拉辛蛋白在纳摩尔浓度中有效，针对培养的血液T. brucei。