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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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，已对大多数现有的抗疟疗法产生广泛耐药性。 氯喹是治疗和预防疟疾的主要药物，它会破坏致病生物体内宿主血红蛋白分解代谢过程中释放的血红素聚合，但氯喹耐药的机制仍不清楚。 攻击氯喹耐药机制但不易受到相同耐药模式影响的新型抗疟药将是非常理想的，而且将有助于理解氯喹耐药机制。 为了实现这一目标，我们合成并表征了一系列能够配位金属的有机支架，包括生物相容性铁 (III)，以生成稳定的化合物，这些化合物具有离域的阳离子电荷，可渗透到细胞内区室中。 先导化合物已证明对氯喹敏感（HB3）和氯喹耐药（Dd2）菌株具有相互的细胞毒活性。 除了其他光谱技术外，还使用质谱法 (FAB) 来分析这些金属药物的分子量。 此外，与目标蛋白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资源的基质辅助激光解吸电离（MALDI）进行评估。 结果将有利于识别这些金属药物靶向的基因。