TARGETING CHLOROQUINE RESISTANCE W/ METAL(III) METALLOPHARMACEUTICALS

使用金属 (III) 金属药物靶向氯喹耐药性

• 批准号: 8361327
• 负责人: Vijay Sharma
• 金额: $ 0.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361327
• 关键词: Antimalarials; Binding; Catabolism; Charge; Child; Chloroquine; Chloroquine resistance; Communicable Diseases; Funding; Gene Targeting; Grant; Heme; Hemoglobin; Iron; Lead; Malaria; Mass Spectrum Analysis; Metals; Molecular Weight; National Center for Research Resources; Organism; Penetration; Plasmodium falciparum; Principal Investigator; Prophylactic treatment; Proteins; Research; Research Infrastructure; Resistance; Resources; Series; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Techniques; United States National Institutes of Health; Universities; Washington; biomedical resource; cost; cytotoxic; killings; polymerization; resistance mechanism; scaffold

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Malaria remains one of the world''s most devastating infectious diseases, afflicting several hundred million people and killing close to two million children each year. Plasmodium falciparum, the most deadly species, has become widely resistant to most available antimalarial therapies. Chloroquine, the mainstay of treatment and prophylaxis of malaria, disrupts polymerization of heme released during catabolism of host hemoglobin within the causative organism, but the mechanisms of chloroquine resistance remain unknown. New antimalarials that attack chloroquine resistance mechanisms, but not susceptible to the same resistance modes would be highly desirable and furthermore, would help in understanding the mechanism(s) of chloroquine resistance. Towards this objective, we have synthesized and characterized a series of organic scaffolds that are capable of coordinating metals, including a bio-compatible iron (III) to generate stable compounds that possess a delocalize d c ationic charge for penetration in the intracellular compartments. The lead compounds have demonstrated reciprocal cytotoxic activity against chloroquine-sensitive (HB3) and chloroquine-resistant (Dd2) strains. In addition to other spectroscopic techniques, mass spectrometry (FAB) has been used to analyze the molecular weight of these metallopharmaceuticals. Further, the compounds that bind irreversibly to the target protein, will be evaluated through matrix-assisted laser desorption ionization (MALDI) at Washington University resource for biomedical and bioorganic mass spectrometry. The results will be beneficial to identify gene(s) targeted by these metallopharmaceuticals.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 疟疾仍然是世界上最具破坏性的传染病之一，每年困扰着数亿人，并导致近200万儿童死亡。恶性疟原虫是最致命的物种，已经对大多数可用的抗疟疾疗法产生了广泛的抗药性。氯喹是治疗和预防疟疾的主要药物，它可以破坏宿主血红蛋白在病原生物体内分解代谢时释放的血红素聚合，但氯喹抗药性的机制尚不清楚。新的抗疟药攻击氯喹抗性机制，但对相同的耐药模式不敏感，这将是非常可取的，并将有助于理解氯喹耐药机制(S)。为此，我们合成并表征了一系列能够与金属配位的有机支架，包括生物相容的铁(III)，以生成稳定的化合物，这些化合物具有离域阳离子电荷，可以穿透细胞内的隔室。这些先导化合物对氯喹敏感(HB3)和抗氯喹(DD2)菌株显示出互惠的细胞毒活性。除了其他光谱技术外，还使用了质谱仪(FAB)来分析这些金属药物的相对分子质量。此外，与目标蛋白质不可逆结合的化合物将通过华盛顿大学生物医学和生物有机质谱学资源的基质辅助激光解吸电离(MALDI)进行评估。这一结果将有助于确定这些金属药物的靶向基因(S)。