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: 8137876
• 负责人: ANDRDEA J BOURDELAIS
• 金额: $ 21.17万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137876
• 关键词: Affinity; Aldehydes; Asthma; Binding; Binding Sites; Biological; 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; Health; 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; 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）：由海洋鞭毛藻生产的反式聚醚类天然产品是已知最有效的非大分子生物制剂之一。短链毒素（PbTxs）和雪卡毒素（CTXs）是已知的唯一高亲和力结合电压门控钠通道（VGSCs） 5号位点的配体。2004年，我们发现了第三类聚醚离子通道调节剂brevenal，它可以抵消5位有毒配体的影响。与短叶草毒素和雪卡毒素不同，短叶草毒素在纳摩尔到皮摩尔浓度范围内是有毒的，就我们所调查的而言，短叶草毒素是无毒的。更重要的是，brevenal是一种拮抗剂，它可以消除、减少或阻止brevenal毒素和雪卡毒素在每一个系统中的作用。受体结合研究表明，brevenal不直接竞争位点5，而是非竞争性地调节PbTx活性。生物实验表明，短叶黄醛在体内对短叶黄毒素和雪卡毒素的毒性作用具有拮抗作用。在绵羊吸入模型中，短静脉阻断pbtx诱导的支气管收缩，导致气管粘液速度增加。实验结果支持对治疗神经毒性贝类中毒（因短叶藻毒素引起的NSP）和雪卡毒素鱼中毒（因雪卡毒素引起的CFP），或更广泛地治疗哮喘、慢性阻塞性肺病或囊性纤维化的影响。总之，brevenal是一个值得研究的分子类。本提案的主要目标是生产半合成的短venal衍生物，a)对短venal受体表现出更高的亲和力（<10 nM）和保留受体选择性，最终能够分离和表征这种新型受体，b)评估合成的短venal衍生物配体在体内模型中对短venal毒素和ciguatoxin的影响表现出更高的功效。本研究的最终目标是鉴定具有治疗离子通道介导疾病潜力的聚醚短链衍生物，特别是针对NSP和CFP，以及那些自然发生的人类疾病，如哮喘、COPD和囊性纤维化，这些疾病已证实存在离子通道介导/功能障碍。与此类似，短静脉受体位点也为治疗性配体的开发提供了新的药物位点。PDF创建与pdfFactory试用版www.pdffactory.com