TARGETING CHLOROQUINE RESISTANCE WITH FE(III) COMPLEXES

使用 FE(III) 复合物对抗氯喹耐药性

• 批准号: 6741458
• 负责人: Vijay Sharma
• 金额: $ 30.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741458
• 关键词: Plasmodium falciparum; Schiff bases; affinity labeling; antimalarial agents; chemical structure function; chloroquine; confocal scanning microscopy; drug design /synthesis /production; drug interactions; drug resistance; drug screening /evaluation; fluorescence microscopy; fluorescent dye /probe; gene expression; genetic polymorphism; immunoelectron microscopy; immunoprecipitation; in situ hybridization; iron compounds; malaria; metal complex; microorganism culture; pharmacokinetics; protein binding; western blottings

Emergence of chloroquine-resistant Plasmodium falciparum species is a major obstacle to the chemotherapy of malaria. In addition to the need for discovery of novel antimalarials, exploration of mechanism(s) of chloroquine resistance has become of paramount importance. Recently, patterns of chloroquine resistance in P. falciparum have been mapped to a 36 kb segment of chromosome 7 harboring a small cluster of genes, including Pfctr, a gene encoding an integral membrane protein with complex polymorphisms. Recently, we have discovered a novel agent, a 3-methoxy-substituted amine phenolate metal(III) complex (MR045), that selectively targets chloroquine-resistant clones associated with specific polymorphisms in this 36 kb segment. This lead compound inhibits the parasite heme polymerization reaction, the same putative target as chloroquine, but traverses the chloroquine resistance mechanism in all strains tested to date. In fact, the antimalarial activity of MR045 maps in perfect linkage with resistance polymorphisms in Pfctr, including the Sudan 106/1 strain, an exceptional case for other candidate genes in this segment. Furthermore, a close analogue now has been discovered, MR082, which shows the exact inverse activity. We propose to further explore structure-activity relationships by synthesis of additional analogues based on this reciprocal pair, identify candidate chloroquine resistance proteins by synthesis of photoaffinity analogues to probe cells and extracts, and localize the drug in cells in situ by incorporation of fluorophores into the motif for correlation with the location of candidate chloroquine resistance proteins. These versatile metal(III) complexes will also be radiolabeled and used in binding, transport and competitive biochemical assays with membrane preparations, digestive vacuoles, and purified PfCTR protein in relation to the chloroquine resistance phenotype. Therefore, these reagents provide unique tools to explore mechanism(s) of chloroquine resistance and provide promising leads for the generation of novel drug candidates that target chloroquine resistant organisms.

恶性疟原虫种类的出现是疟疾化学疗法的主要障碍。 除了发现新型抗疟药的需求外，对氯喹耐药机制的探索也变得至关重要。 最近，恶性疟原虫中氯喹的耐药性模式已映射到36 Kb的段7染色体，该染色体具有一小部分基因，其中包括PFCTR，其中包括一种编码具有复杂多态性的积分膜蛋白的基因。最近，我们发现了一种新颖的药物，即一种3-甲氧基取代的胺苯甲酸金属（III）配合物（MR045），该金属（MR045）有选择地靶向与该36 KB段有关的特定多态性的氯喹耐性克隆。 该铅复合抑制了寄生虫血红素聚合反应，与氯喹相同的推定靶标，但迄今为止所有应测试的菌株中的氯喹耐药机制穿越。实际上，MR045地图与PFCTR中的耐药性多态性的完美链接（包括苏丹106/1菌株）中的抗性活性，这是该部分中其他候选基因的特殊情况。 Furthermore, a close analogue now has been discovered, MR082, which shows the exact inverse activity. 我们建议通过基于此互惠对的其他类似物的合成来进一步探索结构活性关系，并通过合成光接触类似物来探测和提取候选的氯喹耐药性蛋白，并通过将液位载体与候选毒素抗位置抗性互动的基序中的培养基融合到原位，并将其定位在细胞中，并将其定位。 这些多功能金属（III）复合物也将与膜制剂，消化液泡和纯化的PFCTR蛋白相对于氯喹耐药性表型，并将其用于结合，运输和竞争性生化测定。因此，这些试剂提供了独特的工具来探索氯喹耐药性的机制，并为靶向氯喹抗性生物的新型药物候选物的产生提供了有希望的潜在客户。