A Multidisciplinary Approach for the Treatment of Botulinum Intoxication

治疗肉毒杆菌中毒的多学科方法

• 批准号: 9313771
• 负责人: Kim Janda
• 金额: $ 56.62万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-11 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313771
• 关键词: Acetylcholine; Active Sites; Address; Adverse effects; Aminopyridines; Anaerobic Bacteria; Animal Model; Animals; Antibodies; Antitoxins; Attenuated; Biological Assay; Bioterrorism; Bontoxilysin; Botox; Botulinum Toxin Type A; Botulism; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Clinical; Clinical Trials; Clostridium botulinum; Complex; Controlled Environment; Cosmetics; Data; Diagnosis; Disease; Drug Controls; Drug Delivery Systems; Drug Kinetics; Drug Metabolic Detoxication; Dynamin I; Effectiveness; Endocytosis; Endopeptidase K; Enzymes; Event; Exposure to; Family; Food Contamination; Functional disorder; Future; GTP-Binding Protein alpha Subunits, Gs; Goals; Gram-Positive Bacteria; Guanosine Triphosphate Phosphohydrolases; Half-Life; Hand; Human; Immunologics; In Vitro; Induction of neuromuscular blockade; Intervention; Intoxication; Lead; Lethal Dose 50; Life; Light; Liquid substance; Mechanical ventilation; Mediation; Medical; Metalloproteases; Methods; Modeling; Molecular Analysis; Monoclonal Antibodies; Mus; Muscle; Neurons; Neurotoxins; Oral; Outcome; Overdose; Paralysed; Pathology; Patients; Peptide Hydrolases; Peripheral; Pharmaceutical Chemistry; Pharmacology; Phase I Clinical Trials; Poison; Poisoning; Potassium Channel; Procedures; Process; Protease Inhibitor; Proteins; Proteolysis; Reporting; Research; Respiratory Diaphragm; Roentgen Rays; Route; SNAP receptor; Savings; Series; Serotyping; Severities; Study models; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxin; Voltage-Gated Potassium Channel; X-Ray Crystallography; base; biothreat; botulinum; channel blockers; controlled release; cost; disorder prevention; fighting; functional group; high risk; improved; induced pluripotent stem cell; inhibitor/antagonist; interdisciplinary treatment approach; man; molecular modeling; neurotoxicity; scaffold; small molecule; small molecule inhibitor; stem; weapons

Project Summary/Abstract. The clinical signature of botulinum neurotoxin (BoNT) is peripheral neuromuscular blockade and flaccid paralysis, which depending on the serotype (A-G) can last for months. BoNTs are the most toxic proteins known to man and have been classified by the Centers for Disease Control and Prevention as one of the six highest-risk biothreat agents. Despite high potential as a bioterrorist weapon, BoNTs are widely used in medical and cosmetic procedures (i.e., Botox). However, even under a controlled environment unwanted side effects have been reported and in some cases severe life-threatening disorders. Clinical intervention of BoNT poisoning is complicated by not only its extreme toxicity but also its long half-life (months for BoNT/A). Currently a botulinum heptavalent antitoxin (BAT) is the only approved medical intervention, yet, has limited value since antibodies can only neutralize circulating toxin, which is negated once cellular poisoning takes place. There are no pharmacologic antagonists available that act once cellular intoxication takes place and none that even advanced to Phase I Clinical Trials. Prohibitive as developing a therapeutic might seem we have shown that BoNT/A intoxication can be attenuated using a synergistic combination of an antibody and a pharmacological antagonist. As significant as this finding has been to the BoNT field, a further mastery would be the use of singular pharmacological agents fashioned to attenuate BoNT/A's toxicity. We currently possess several classes of small molecule inhibitors that can intercede at three junctions critical to BoNT's pathology: SNARE protein cleavage, neurotoxin endocytosis, and blockade of acetylcholine release. From this arsenal we have discovered molecules engendered to block multiple processes associated with BoNT/A neurotoxicity. Impressively, this dual inhibitor-mechanism strategy provides the first small molecule that can extend time to death from a BoNT/A post exposure occurrence. We have established how potassium channel blockade can provide full sustenance in the reversal of paralysis for post- intoxication of BoNT/A. For this research we offer the molecules 3,4-diaminopyridine (3,4-DAP) and 3,4,5- triaminopyridine (3,4,5-TAP); both are highly effective for BoNT/A rescue. However, aminopyridine's effectiveness is severely compromised by their short half-life. We will address this limitation within our proposed studies. Finally, as a means to augment our small molecule pharmacological antagonist research initiative we will use medicinal chemistry, X-ray crystallography and pharmacokinetics to develop both greater selectivity and more potent inhibitors against the botulinum neurotoxins. The successful integration of our research goals will bring the complex and challenging problem of treating botulinum toxicity toward a clinically viable treatment.

项目摘要/摘要。肉毒神经毒素（BONT）的临床特征是周围 根据血清型（A-G）的不同，神经肌肉阻滞和脆性瘫痪可以持续数月。 BONT是人类已知的最有毒蛋白质，已被疾病控制中心分类 并作为六种最高风险的生物治疗剂之一。尽管作为生物恐怖主义武器的潜力很高，但 BONT广泛用于医学和化妆程序（即肉毒杆菌毒素）。但是，即使在受控的 已经报道了环境不良的副作用，在某些情况下，严重威胁生命的疾病。 骨中毒的临床干预不仅因其极端毒性，而且其长期寿命而变得复杂 （BONT/A的月份）。目前，肉毒杆菌六价抗毒素（BAT）是唯一获得批准的医疗 但是，干预措施的价值有限，因为抗体只能中和循环毒素，这一次是否定的 细胞中毒发生。没有可用的药理学拮抗剂可起作用 中毒发生了，甚至没有任何进展到I期临床试验。过于发展 治疗可能似乎已经证明，可以使用协同作用来减弱BONT/A中毒 抗体和药理学拮抗剂的组合。这一发现对 BONT FIELD，进一步的掌握将是使用以衰减的奇异药理剂 BONT/A的毒性。目前，我们拥有几类的小分子抑制剂，可以在三个处介入 对BONT病理至关重要的连接：裂解蛋白质裂解，神经毒素内吞作用和阻断 乙酰胆碱释放。从这个武器库中，我们发现了封闭多个的分子 与BONT/A神经毒性相关的过程。令人印象深刻的是，这种双重抑制剂机制策略提供了 第一个可以从BONT/A后发生的小分子延长时间。我们有 确定了钾通道封锁如何​​在瘫痪的逆转中提供全部寄生 BONT/A的中毒。在这项研究中，我们提供分子3,4-二氨基吡啶（3,4-DAP）和3,4,5-- 曲安培丁（3,4,5-TAP）;两者对于BONT/A营救都非常有效。但是，氨基吡啶的 他们的半衰期造成了严重损害有效性。我们将在我们的内部解决这个限制 拟议的研究。最后，作为增强我们的小分子药理拮抗剂研究的一种手段 主动性我们将使用药物化学，X射线晶体学和药代动力学来发展更大的 选择性和对肉毒神经毒素的更有效抑制剂。我们的成功整合 研究目标将带来复杂而充满挑战的问题，即将肉毒杆菌毒性治疗到临床上 可行的治疗。