TARGETING CHLOROQUINE RESISTANCE WITH FE(III) COMPLEXES

使用 FE(III) 复合物对抗氯喹耐药性

• 批准号: 2884553
• 负责人: Vijay Sharma
• 金额: $ 24.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-15 至 2001-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2884553
• 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 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 cg2, a gene encoding a unique 330 kDa 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. Therefore, this agent can be a tool to explore mechanism(s) of chloroquine resistance and provides a promising lead for generation of novel drug candidates for use in the chemotherapy of chloroquine resistant disease. We have observed that slight variations in the position of functionalities in the peripheral regions of the organic scaffold, not the central metal core, impart the unique targeting properties to MR045. Therefore, we propose to further explore structure-activity relationships by synthesis of additional analogues based on this lead compound, identify candidate chloroquine resistance proteins by synthesis of photoaffinity analogues to probe cell extracts, and localize the drug in cells in situ by incorporation of fluorophores in 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 membranes, digestive vacuoles, and purified CG2 in relation to the chloroquine resistance phenotype. While providing novel reagents as biochemical probes of the mechanism(s) of chloroquine resistance, this project also will provide candidate drugs 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7染色体段7，其中含有一小部分基因，包括CG2，包括CG2，它是编码具有复杂多态性的独特330 kDa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。因此，该试剂可以是探索氯喹耐药机制的工具，并为生成新型药物候选物提供了有前途的铅，用于用于化学疗法的氯喹耐药性疾病。 我们已经观察到，有机支架的外围区域的功能位置的略有变化，而不是中央金属芯，将唯一的靶向性能赋予了MR045。 因此，我们建议通过基于这种铅化合物的其他类似物的合成来进一步探索结构活性关系，通过合成光附子类似物来探测细胞提取物，鉴定候选氯喹耐药性蛋白，并通过将氟载体掺入与候选蛋白的位置相处的基序中，通过将氟载体融合到原位的细胞中。 这些多功能金属（III）配合物也将与膜，消化液泡和纯化的CG2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。 在提供新的试剂作为氯喹耐药机制的生化探针时，该项目还将提供靶向氯喹耐药生物的候选药物。

项目成果

Interrogation of multidrug resistance (MDR1) P-glycoprotein (ABCB1) expression in human pancreatic carcinoma cells: correlation of 99mTc-Sestamibi uptake with western blot analysis.

• DOI: 10.1097/mnm.0000000000000158
• 发表时间: 2014-10
• 期刊: Nuclear medicine communications
• 影响因子: 1.5
• 作者: Harpstrite SE;Gu H;Natarajan R;Sharma V
• 通讯作者: Sharma V

Metalloprobes: synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells.

• DOI: 10.1016/j.jinorgbio.2007.04.013
• 发表时间: 2007-10
• 期刊: Journal of inorganic biochemistry
• 影响因子: 3.9
• 作者: Scott E. Harpstrite;Julie L. Prior;N. Rath;V. Sharma

Therapeutic drugs for targeting chloroquine resistance in malaria.

针对疟疾氯喹耐药性的治疗药物。

• DOI: 10.2174/1389557053544029
• 发表时间: 2005
• 期刊: Mini reviews in medicinal chemistry
• 作者: Sharma,Vijay

A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK).

• DOI: 10.1021/ol300728a
• 发表时间: 2012-07-20
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Sundaram GS;Harpstrite SE;Kao JL;Collins SD;Sharma V
• 通讯作者: Sharma V

Synthesis, characterization, and molecular structure of a gallium(III) complex of an amine-phenol ligand with activity against chloroquine-sensitive Plasmodium falciparum strains.

具有抗氯喹敏感性恶性疟原虫菌株活性的胺-苯酚配体镓（III）络合物的合成、表征和分子结构。

• DOI: 10.1016/s0162-0134(02)00592-5
• 发表时间: 2003
• 期刊: Journal of inorganic biochemistry
• 影响因子: 3.9
• 作者: Ocheskey,JosephA;Polyakov,ValeryR;Harpstrite,ScottE;Oksman,Anna;Goldberg,DanielE;Piwnica-Worms,David;Sharma,Vijay
• 通讯作者: Sharma,Vijay