Development of High Affinity Analogues of Brevenal: Novel Molecular Probes for Ne

Brevenal 高亲和力类似物的开发：新型 Ne 分子探针

• 批准号: 7979382
• 负责人: ANDRDEA J BOURDELAIS
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF NORTH CAROLINA WILMINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979382
• 关键词: Affinity; Aldehydes; Asthma; Binding; Binding Sites; Biological Assay; Biological Factors; Biological Testing; Brain; Breathing; Brevenal; Bronchoconstriction; Catecholamines; Cell Survival; Cells; Chromaffin Cells; Chronic Obstructive Airway Disease; Ciguatera Poisoning; Ciguatoxins; Competitive Binding; Cystic Fibrosis; Data; Development; Dinophyceae; Disease; Electrons; Electrophysiology (science); Event; Exhibits; Exposure to; Family; Functional disorder; Goals; Human; In Vitro; Ingestion; Ion Channel; Lead; Ligand Binding; Ligands; Lung diseases; Marines; Mediating; Mediation; Modeling; Modification; Molecular; Molecular Probes; Mucous body substance; Neurotoxins; Pharmaceutical Preparations; Poisoning; Rattus; Reaction; Research; Respiratory distress; Sea; Sheep; Shellfish; Side; Site; Sodium; Sodium Channel; Synaptosomes; System; Testing; Therapeutic; Toxic effect; Toxin; analog; base; brevetoxin; cytotoxicity; diene; improved; in vitro Model; in vivo; nervous system disorder; neurotoxic; novel; patch clamp; prevent; public health relevance; receptor; receptor binding; respiratory; stoichiometry; voltage

DESCRIPTION (provided by applicant): The trans-syn class of marine polyether natural products produced by marine dinoflagellates are some of the most potent non-macromolecular biologicals known. Brevetoxins (PbTxs) and ciguatoxins (CTXs) are well known as the only ligands known to bind to site 5 on voltage-gated sodium channels (VGSCs) with high affinity. In 2004, we discovered brevenal, a third class of polyether ion channel modulator which counteracts the effects of site 5 toxic ligands. Unlike brevetoxins and ciguatoxins which are toxic in the nanomolar to picomolar concentration ranges, brevenal is non-toxic as far as we have investigated. More importantly, brevenal is an antagonist which negates, reduces, or prevents the effects of brevetoxin and ciguatoxin in every system examined. Receptor binding studies have demonstrated that brevenal does not directly compete for site 5 but non-competitively regulates PbTx activity. Biological testing showed brevenal to be antagonistic to the toxic effects of brevetoxins and ciguatoxins in vivo. In sheep inhalation models, brevenal blocks PbTx-induced bronchoconstriction and leads to increased tracheal mucous velocity. Implications for treatment of neurotoxic shellfish poisoning (NSP due to brevetoxin) and ciguatera fish poisoning (CFP due to ciguatoxin), or more broadly for the treatment of asthma, COPD or Cystic Fibrosis are supported through experimental results. In short, brevenal is a molecular class worthy of study. Key objectives of this proposal are to produce semi-synthetic brevenal derivatives that a) exhibit increased affinity (<10 nM) and retention of receptor selectivity for the brevenal receptor, ultimately enabling the isolation and characterization of this novel receptor, and b) assess synthetically-produced derivative brevenal ligands which exhibit improved efficacy against the effects of brevetoxin and ciguatoxin in in vito models. The ultimate goal of this research is to identify polyether brevenal derivatives with potential for use in the treatment ion-channel mediated disorders, with specific intent towards NSP and CFP, and for those naturally occurring human maladies like asthma, COPD, and cystic fibrosis, for which there is a demonstrated ion channel mediation/dysfunction. By analogy, the brevenal receptor site which will become more fully characterized as a result of this application provides a new drug locus for therapeutic ligand development. PDF created with pdfFactory trial version www.pdffactory.com PUBLIC HEALTH RELEVANCE: Ingestion or inhalation of the marine polyether compounds, brevetoxins or ciguatoxins, can lead to respiratory difficulty and prolonged neurological disorders for which there is, currently, no known treatment or cure. Brevenal, a natural product derived from the marine dinoflagellate Karenia Brevis has been shown to block effects of brevetoxins and ciguatoxins. Synthesis of highly potent brevenal derivatives could lead to compounds with the potential for treating exposure to environmental neurotoxins and aid in the identification of a new drug locus for treatment of pulmonary disorders such as asthma, cystic fibrosis and COPD. PDF created with pdfFactory trial version www.pdffactory.com

描述（由申请人提供）：海洋鞭毛藻产生的海洋多醚天然产物的反式同盟类是已知的最有效的非巨型分子生物学。 Brevetoxins（PBTXS）和CIGUATOXIN（CTXS）是唯一已知与具有高亲和力的电压门控钠通道（VGSC）结合位点5的配体。 2004年，我们发现了Brevenal，这是第三类聚醚离子通道调节剂，它抵消了位点5有毒配体的影响。与纳摩尔至皮摩尔浓度范围有毒的Brevetoxins和ciguatoxin不同，据我们研究，百素浓度范围是无毒的。更重要的是，Brevenal是一个对手，可抵消，降低或防止在所检查的每个系统中Brevetoxin和ciguatoxin的影响。受体结合研究表明，头脑没有直接竞争位点5，而是非竞争性调节PBTX活性。生物学测试表明，短素与体内的Brevetoxins和ciguatoxins的毒性作用是拮抗的。在绵羊吸入模型中，短毛阻塞PBTX诱导的支气管收缩并导致气管粘液速度增加。通过实验结果支持对治疗神经毒性贝类中毒（由于Brevetoxin引起的NSP）和CIGUATERA鱼中毒（CFP）的影响，或更广泛地治疗哮喘，COPD或囊性纤维化的治疗。简而言之，Brevenal是值得研究的分子类。该提案的关键目标是产生半合成的百合衍生物，a）表现出增强的亲和力（<10 nm），并保留了对金融受体的受体选择性的保留，最终使这种新型受体的隔离和表征能够隔离和表征B），并评估了对衍生品的衍生品，这些衍生性均具有对衍生品的拟合性，这些衍生品与促进性的良好型良好的有效性，对有效的有效性促进了生效的生效性，这些元素对生效的有效性促进了促进性，这些元素促进了促进的效果，以促进效率促进良好的效果，以促进效率促进良好的效果，并具有对衍生性的效果。 In Vito模型。这项研究的最终目的是鉴定具有用于治疗离子通道介导的疾病的潜力，对NSP和CFP的特定意图，以及对于那些自然存在的人类疾病（如哮喘，COPD和囊性纤维化）的特定意图，其中有一个证明的离子通道介质介质/囊性纤维化。类比，由于本应用的结果，它将变得更充分地表征的短素受体部位为治疗配体发育提供了新的药物基因座。 PDF使用pdffactory试用版本www.pdffactory.com创建 公共卫生相关性：摄入或吸入海洋聚醚化合物，Brevetoxins或雪茄毒素，可能会导致呼吸困难和延长的神经系统疾病，目前尚无已知治疗或治疗。 Brevenal是一种自然产品，它衍生自海洋鞭毛虫Karenia brevis已显示可阻断Brevetoxins和ciguatoxins的作用。高度有效的头衍生物的合成可能会导致具有治疗环境神经毒素暴露的可能性的化合物，并有助于鉴定出一种新药物基因座，以治疗哮喘，囊性纤维化和COPD等肺部疾病。 PDF使用pdffactory试用版本www.pdffactory.com创建