Heparin-mimetic sulfated oligoxylan inhibitors of malaria parasites

疟疾寄生虫的肝素模拟硫酸化寡聚木聚糖抑制剂

• 批准号: 8371075
• 负责人: AUDREY L STONE
• 金额: $ 1.78万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8371075
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Agreement; Anti-malarial drug resistance; Anticoagulants; Antimalarials; Biological Assay; Biological Models; Biopolymers; Cells; Cerebral Malaria; Cerebrum; Chemicals; Child; Collaborations; Confidentiality; Culicidae; Data; Development; Disease; Distress; Dose; Erythrocytes; Family; Fractionation; Glucuronic Acids; Goals; Growth; HIV; HIV Infections; HIV-1; Health Sciences; Hemorrhage; Heparin; Heparitin Sulfate; Hepatocyte; Human; Hydroxyl Radical; Immunity; In Vitro; Incidence; Inorganic Sulfates; Invaded; Knowledge; Lead; Libraries; Ligands; Link; Literature; Liver; Maintenance; Malaria; Malaria Vaccines; Medical; Methods; Molecular; Nature; Parasite resistance; Parasites; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Preventive; Process; Property; Protocols documentation; Public Health; Reporting; Research; Role; Sampling; Science; Specificity; Spectroscopy, Fourier Transform Infrared; Sporozoites; Staging; Structure; System; Techniques; Testing; Thrombin; Unspecified or Sulfate Ion Sulfates; Vaccine Design; Vaccines; Variant; Xylans; Xylose; base; biological systems; combinatorial; density; design; dosage; drug development; improved; inhibitor/antagonist; killings; mimetics; mimicry; novel; pathogen; preclinical study; prevent; programs; receptor; sugar

Severe and cerebral malaria kill about 2-3 million or more people per year 90 % are young children. There is no preventive vaccine, and the malaria parasites are increasingly resistant to anti-malarial drugs. The initial infective process of the malaria parasite in humans is between the invading parasite and hepatocytes of the host. In several studies, the heparin/heparan sulfate (H/HS) receptor systems have been implicated in this invasion. We previously applied our combinatorial family of heparin-mimetic S-oligoS (See HD 001315-14,16) to characterize their in vitro inhibition capacities against malaria parasites in vitro and revealed that the heparin-based inhibition of P. yoelii sporozoite (freshly isolated from infected mosquitoes) invasion of hepatocytes was governed by a degree of structural specificity and was concentration dependent. Two highly active library components (Cp) were identified, Cp6 and 11, with estimated EC 50s of 3.5 and 5 micromolar, resp; Cp11 had earlier displayed negligible heparin-anticoagulant capacity against thrombin (which occasionally causes bleeding when pharmaceutical heparin is administered clinically). Inhibitory Capacity Further studies of the inhibitory capacities of Cp11 and 6 against liver stage development of malaria parasites in vitro are planned. Our renewed mutual Confidentiality Agreement with Bene Arzneimittel, Munich, D.R. has provided another large lot of heparin-mimetic pharmaceutical starting material for preparation of additional Cp11 as well as our HIV-1 inhibitors, SOLIS and the Cp 8 group. Development of an enlarged investigative preparation of Cp11 is ongoing to insure adequate fractionation results and agreement between the two batches (See 1 ZIA HD001315-16 DIR). Structural Study We found by spectroscopic and chemical analyses that the H/HS-mimetic S-OligoS Cps besides carrying sulfate groups on up to 85 percent of the sugar hydroxyls (high anionic density) also contain a specific tetrasaccharide motif of three 1-4 beta linked xyloses and a 1-2 alpha-linked glucuronic acid, one third or less O methylated (as a branch on the xylan chain). In addition, the number of these alternate forms appears to increase with increase in mass of the Cp. Alternate forms induce specific distance and angle alterations in the otherwise uniform S-OligoS chain properties. Such a motif could accommodate the subtle specific variations in geometries involving sulfates that are required for mutifunctional mimicry of the heparins. Further elucidation of the Cp11 structure might enable application of advanced high throughput methods in further drug development. Cp11 and 6 samples are in progress for current study by FTIR and NMR analyses. Cerebral Malaria We anticipate testing our H/HS-mimetic combinatorial family for a potential agent against the acute cerebral distress and fatality in patients with cerebral malaria as soon as collaboration with a malarial parasitologist is arranged. "Copathogenesis" Recently developed statistical analysis was used by clinicians to calculate findings (Science 319:1603 2006) that HIV infection in malaria endemic regions is spread at a rate 8 percent higher than in other regions where HIV-AIDS is on the rise due to an unexplained vulnerability of either patient to the second pathogen. We had suggested previously that co-treatment of malaria and HIV-AIDS would be feasible because of the close similarity in the physicochemical properties of the respective S-oligoS inhibitors. Our preliminary in vitro study on combined dosing of Cp11 and SOLIS (S-OligoS malaria parasite and HIV-1 inhibitors, resp.) confirmed the compatibility of the two potential drugs in assays using CM-SS cells. Given the complexity of the known or novel biological systems which may be involved, the data are currently interpreted based on several biological models to generate appropriately designed assays which will be used with the Cp11 to elucidate this "copathogenesis".

严重和脑疟疾每年杀死约2-3万人或更多的人90％是幼儿。没有预防性疫苗，疟疾寄生虫越来越抗性抗疟疾药物。人类疟原虫寄生虫的最初感染过程在宿主的入侵寄生虫和肝细胞之间。在几项研究中，肝素/肝素硫酸盐（H/HS）受体系统已与这种入侵有关。以前，我们以前应用了肝素模拟的S-Oligos（见HD 001315-14,16）的组合家族，以表征其体外抑制能力对疟疾的体外体外抑制能力，并表明基于肝素的sporozoite（来自sporozoite septed Mosquocite of Mosquoce of Aft of apation of apation of apation of apation of apation of apation of apation of apation of apation of apation of a。特异性和浓度取决于。确定了两个高度活跃的文库组件（CP），即CP6和11，估计EC 50s为3.5和5微摩尔； CP11早些时候表现出对凝血酶的肝素 - 抗凝蛋白的能力微不足道（在临床上施用药物肝素时，偶尔会导致出血）。 抑制能力 计划进一步研究CP11和6对体外疟疾寄生虫肝脏阶段发育的抑制能力。我们与Bene Arzneimittel，Munich，D.R。更新了共同的机密协议提供了另一种大量的肝素模拟药物起始材料，用于制备其他CP11以及我们的HIV-1抑制剂，SOLIS和CP 8组。正在进行扩大的CP11调查制备，以确保两批批次之间的足够分馏结果和一致性（请参阅1 Zia HD001315-16 DIR）。 结构研究 我们通过光谱和化学分析发现，除了在多达85％的糖羟基（高阴离子密度）上携带硫酸基团的H/HS模拟S-橄榄酸CP，还包含特定的四糖序列的三个1-4个β链球链球链球链球和1-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2. 链）。另外，这些替代形式的数量似乎随着CP质量的增加而增加。替代形式诱导特定的距离和角度变化，在原本均匀的S-Oligos链特性中。这样的基序可以适应涉及硫酸硫酸盐的几何形状的细微特异性变化，而硫酸盐是肝素模仿所需的。对CP11结构的进一步阐明可以使高级高通量方法在进一步的药物开发中应用。 FTIR和NMR分析正在进行CP11和6个样本。 脑疟疾 我们预计，一旦安排了与疟疾的疟疾疟疾患者，我们的HS/HS模拟组合家族对急性脑遇难和死亡的潜在药物进行了测试。 “共同发生” 临床医生使用了最近开发的统计分析来计算发现（科学319：1603 2006），即疟疾流行区域的HIV感染以比其他艾滋病毒艾滋病因任何一种患者对第二种病原体的无法解释的脆弱性而增加的速度增长8％。我们以前曾建议，由于各个S-橄榄石抑制剂的物理化学特性的相似性，疟疾和HIV-AID的共同治疗是可行的。我们对CP11和Solis（S-橄榄虫寄生虫和HIV-1抑制剂的联合剂量的联合剂量）的初步研究证实了两种潜在药物在使用CM-SS细胞中的兼容性。鉴于可能涉及的已知或新型生物系统的复杂性，目前根据几种生物学模型来解释数据，以生成适当设计的测定法，这些测定法将与CP11一起使用，以阐明这种“共同致病发生”。