Therapeutic targeting of malarial placental cytoadherence

疟疾胎盘细胞粘附的治疗靶向

基本信息

批准号：
9097541
负责人：
CHANNE D GOWDA
金额：
$ 48.52万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097541
关键词：
Adherence Adhesives Adult Affinity Africa Amino Acids Antibodies Area Binding Binding Sites Biological Assay Biological Process Carbohydrates Cell surface Cells Cessation of life Chondroitin Sulfate A Chondroitin Sulfate Proteoglycan Chondroitin Sulfates Clinical Development Disease Elements Erythrocyte Membrane Erythrocytes Family Fetus Fluorescence Anisotropy Functional disorder Future Glycosaminoglycans Goals Health Heparin Hybrids Immunity Indium Infant Infection Inflammation Inorganic Sulfates Knowledge Label Length Libraries Ligands Location Low Birth Weight Infant Malaria Measures Mediating Mothers Natural Products Newborn Infant Oligosaccharides Parasites Pattern Pharmaceutical Preparations Phenotype Placenta Plasmodium falciparum Plasmodium falciparum erythrocyte membrane protein 1 Positioning Attribute Preclinical Drug Evaluation Pregnancy Pregnant Women Prevention Protein Region Proteins Reagent Research Research Personnel Resistance Risk Screening Result Structure Structure-Activity Relationship Surface Testing Therapeutic Tissues Unspecified or Sulfate Ion Sulfates Vaccines Variant Woman Work base biochemical model density design drug development effective therapy extracellular fluorophore high throughput screening inhibitor/antagonist innovation insight interest member mimetics novel novel therapeutics placental malaria pregnant prevent receptor research study screening small molecule inhibitor sulfation therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Plasmodium falciparum infection during pregnancy results in placental malaria (PM). In Africa alone, ~25 million women yearly are at risk of developing PM, which causes ~100,000 infant and tens of thousand maternal deaths. Low birth weight is common in PM and these newborns are highly vulnerable to death from subsequent malaria or other infections. Although people in endemic areas will have acquired protective immunity against malaria by their adulthood, women are susceptible to severe malaria during pregnancy. This is due to the adherence in the placenta of an antigenically distinctive P. falciparum phenotype. So women who have never been pregnant have no immunity to this parasite phenotype. In their first and second pregnancies women infected with P. falciparum, the adherent parasites are selected in the placenta, grow rapidly, allowing infected red blood cells (RBCs) to accumulate to high density in the placenta. This results in inflammation and placental dysfunction, causing PM. An effective treatment to prevent or treat PM is essential, but is not currently available. The parasite exports a variant adhesive protein called VAR2CSA, a member of Plasmodium falciparum erythrocyte membrane protein 1 family, that is displayed on the erythrocyte surface. The ectodomain of VA2CSA mediates the binding of IRBCs to 12-mer motifs of the chondroitin 4-sulfate (C4S) moieties of the CSPG receptor in the placenta. Women who have acquired inhibitory anti-VAR2CSA antibodies during prior pregnancies are resistant to PM and deliver healthy babies, indicating that blocking of IRBC adherence is a suitable strategy to treat PM. However, VAR2CSA is a highly polymorphic and so, obtaining a viable vaccine requires rationale design based on the knowledge of conserved C4S-binding site. An alternative approach is to develop adherence-blocking inhibitors. Since VAR2CSA is on the IRBC surface and is accessible for even highly polar molecules, this is predicted to be highly promising strategy. Accordingly, the goals of this proposal are to: (i) chemically synthesize the C4S 12-mers containing two sulfate residues at specific positions and a library of chondroitin sulfate oligosaccharides of different size and sulfation patterns. This will enable us to identify the optimally binding oligosaccharide and critical interactions involved in VAR2CSA-C4S binding; (ii) Using the novel and sensitive C4S 12-mer-based fluorescence anisotropy assay that we have already developed, we will screen drug and glycosaminoglycan mimetic libraries to identify, by high-throughput screening, small molecule inhibitors that block VAR2CSA-C4S binding and validate the inhibitors by a cell-based assay (iii) characterize the C4S-binding sites in VAR2CSA to identify the interacting amino acid residues. The results are expected to provide critical information necessary for developing therapeutics for PM. The long-term objective is to develop small molecule inhibitors that can be used for PM treatment.

描述（由适用提供）：妊娠期间恶性疟原虫感染导致疟原虫疟疾（PM）。仅在非洲，每年约有2500万妇女有发展PM的风险，这会导致约100,000名婴儿和数以万计的生物死亡。低出生体重在PM中很常见，这些新生儿非常容易受到随后的疟疾或其他感染的死亡。尽管内在地区的人们成年后将获得对疟疾的保护免疫，但妇女在怀孕期间容易受到严重疟疾的影响。这是由于抗原独特的恶性疟原虫表型的粘附性。因此，从未怀孕的女性对这种寄生虫表型没有免疫学。在感染恶性疟原虫的第一和第二孕妇中，选择了粘层寄生虫，迅速生长，允许感染的红细胞（RBC）积聚到Pleceta中的高密度。这会导致炎症和局部功能障碍，导致PM。预防或治疗PM的有效治疗方法至关重要，但目前尚不可用。寄生虫导出一种称为VAR2CSA的变体粘合剂蛋白，该蛋白是恶性疟原虫红细胞膜蛋白1家族的成员，该蛋白在红细胞表面上显示。 VA2CSA的胞外域培养了IRBC与Pleceta中CSPG受体的软骨素4-硫酸盐（C4S）部分的12-Mer基序的结合。在怀孕期间获得抑制性抗VAR2CSA抗体的妇女对PM具有抵抗力并提供健康的婴儿，这表明阻止IRBC依从性是治疗PM的合适策略。但是，VAR2CSA是一种高度多态性的，因此，获得可行的疫苗需要基于保守的C4S结合位点的知识的理由设计。另一种方法是开发粘附抑制剂。由于VAR2CSA位于IRBC表面，即使是高度极性分子也可以访问，因此这被预测为高度希望的策略。据此，该提案的目标是：（i）化学合成C4S 12-Mers，其中包含两个硫酸盐在特定位置保留的C4S和一个不同尺寸和硫酸化模式的硫酸盐硫酸盐寡糖库。这将使我们能够确定VAR2CSA-C4S结合中涉及的最佳结合寡糖和关键相互作用。（ii）使用我们已经开发的新型和敏感的C4S基于12-Mer的荧光各向异性测定，我们将筛选药物和糖胺聚糖模拟库，通过高通量筛选，通过高通量筛选，小分子抑制剂，以阻止VAR2CSA-C4结合抑制剂并验证基于抑制剂（III）（III）（III）（III）（III）（III）。 VAR2CSA确定相互作用的氨基酸保留。预计结果将为PM开发治疗所需的重要信息。长期目标是开发可用于PM治疗的小分子抑制剂。