Saxitoxin-Antibody Conjugates as Tools for Na+ Ion Channel Study and Therapeutics

石房蛤毒素-抗体缀合物作为钠离子通道研究和治疗的工具

• 批准号: 7874774
• 负责人: Justin Du Bois
• 金额: $ 23.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874774
• 关键词: Acute; Adult; Adverse effects; Amino Acids; Anesthesia procedures; Antibodies; Ataxia; Binding; Binding Sites; Biochemical; Bupivacaine; Cells; Characteristics; Chronic; Clinical; Communication; Confusion; Congenital Pain Insensitivity; Dependence; Development; Drowsiness; Drug Design; Drug Prescriptions; Drug or chemical Tissue Distribution; Electrophysiology (science); Engineering; Esthesia; Etiology; Evaluation; Family; Fentanyl; Generations; Genes; Goals; Hydrocodone; Hydromorphone; Hyperalgesia; Individual; Injection of therapeutic agent; Integral Membrane Protein; Ion Channel; Ions; Lead; Lidocaine; Ligation; Link; Local Anesthetics; Maleimides; Mediating; Medicine; Molecular; Molecular Structure; Molecular Weight; Monoclonal Antibodies; Morphine; Mutagenesis; National Institute of Drug Abuse; Nausea; Neuraxis; Neurons; Nociception; Numbness; Opioid; Opioid Analgesics; Opioid Receptor; Oral cavity; Pain; Pain management; Pakistan; Pattern; Pharmaceutical Preparations; Pharmacology; Physiology; Polyethylene Glycols; Postoperative Period; Property; Protein Isoforms; Proteins; Recombinants; Risk; Saxitoxin; Signal Transduction; Site; Sodium Channel; Sulfhydryl Compounds; Surface; Techniques; Therapeutic Studies; Tramadol; United States; Variant; Ventilatory Depression; addiction; antibody conjugate; antibody engineering; chemotherapy; chronic neuropathic pain; chronic pain; design; drug of abuse; efficacy testing; extracellular; functional group; inhibitor/antagonist; interest; loss of function mutation; neuronal excitability; next generation; novel therapeutics; programs; protein complex; public health relevance; ropivacaine; small molecule; success; tool; voltage; voltage clamp

DESCRIPTION (provided by applicant): Opioid analgesics, such as morphine, hydromorphone and fentanyl, are broadly prescribed for the management of acute, post-operative and chronic pain. Despite this widespread clinical use, a number of side effects persist including drowsiness, confusion, nausea, hyperalgesia and respiratory depression. Opioids are also highly addictive, and considered drugs of abuse by the NIDA. We wish to develop new pharmacological tools for interrogating specific biochemical mechanisms that underlie pain sensation with the longer-term goal of revealing next-generation therapeutics for pain treatment. Voltage-gated Na+ ion channels are integral membrane proteins responsible for electrical communication between cells. Ten mammalian genes have been sequenced that encode for ten different channel isoforms (NaV1.1- 1.9 and NaX), each having unique biophysical characteristics, and cellular and tissue distribution patterns. Drugs that inhibit NaVs non-specifically (e.g., lidocaine) find application as short-lasting, local anesthetics, but are less than desirable for any type of systemic or chronic use. A compelling body of evidence, however, suggests that specific inhibition of a single NaV isoform could reduce pain sensitivity without the accompanying side effects (numbness, ataxia) associated with local anesthetic treatments (and without chance of addiction, as noted with opioids). Similarities in the macromolecular structures of the nine NaV isoforms have thwarted most efforts to develop drugs that function as antagonist against only a single channel subtype. Our approach will capitalize on the highly specific binding of a monoclonal antibody engineered to target a single NaV isoform. We envision utilizing antibodies raised against NaV1.7, a channel isoform of particular interest as a target for pain treatment. Ion conduction will be inhibited by covalently linking to this antibody a potent, small molecule channel antagonist. Saxitoxin is a low molecular weight, naturally occurring product that acts with nanomolar potency on NaV1.1-1.4, 1.6, and 1.7 by lodging in the outer mouth of the channel pore. Strategies will be developed for conjugating modified forms of (+)-saxitoxin to the antibody and for testing the efficacy of these agents as isoform-specific blockers of NaV function. The success of this program will provide: 1) a tool that can be used to validate NaV1.7 as a target for pain treatment; 2) a novel therapeutic lead in the form of an antibody-small molecule conjugate; and 3) a blueprint for preparing specific inhibitors of other NaV isoforms. PUBLIC HEALTH RELEVANCE: Opioid analgesics, such as morphine, cause a range of side effects and are subject to abuse, yet remain the most frequently prescribed drugs for the treatment of pain. We wish to develop new pharmacological tools that act by intervening with specific pain-producing signals in order to gain a deeper understanding of the etiology of pain. Results from these studies could help guide the development of next-generation therapies for pain management.

描述（由申请人提供）：阿片类镇痛药，如吗啡、氢吗啡酮和芬太尼，广泛用于治疗急性、术后和慢性疼痛。尽管这种广泛的临床使用，一些副作用持续存在，包括嗜睡，意识模糊，恶心，痛觉过敏和呼吸抑制。阿片类药物也具有高度成瘾性，并被NIDA视为滥用药物。我们希望开发新的药理学工具，用于询问疼痛感觉背后的特定生化机制，长期目标是揭示下一代疼痛治疗方法。电压门控Na+离子通道是负责细胞间电通信的膜蛋白。已经对编码十种不同通道亚型（NaV1.1- 1.9和NaX）的十种哺乳动物基因进行了测序，每种通道亚型具有独特的生物物理特征以及细胞和组织分布模式。非特异性抑制NaV的药物（例如，利多卡因）可用作短暂的局部麻醉剂，但对于任何类型的全身或长期使用都不太理想。然而，令人信服的证据表明，对单一NaV亚型的特异性抑制可以降低疼痛敏感性，而不会伴随与局部麻醉治疗相关的副作用（麻木，共济失调）（并且没有成瘾的机会，如阿片类药物所述）。九种NaV亚型的大分子结构的相似性阻碍了开发仅针对单一通道亚型的拮抗剂的药物的大多数努力。我们的方法将利用工程化以靶向单个NaV同种型的单克隆抗体的高度特异性结合。我们设想利用针对NaV1.7（一种特别感兴趣的通道亚型）产生的抗体作为疼痛治疗的靶标。离子传导将通过与该抗体共价连接有效的小分子通道拮抗剂来抑制。石房蛤毒素是一种低分子量的天然产物，通过滞留在通道孔的外口，以纳摩尔效力作用于NaV1.1-1.4、1.6和1.7。将开发用于将（+）-石房蛤毒素的修饰形式缀合至抗体并用于测试这些药剂作为NaV功能的亚型特异性阻断剂的功效的策略。该计划的成功将提供：1）可用于验证NaV 1.7作为疼痛治疗靶点的工具; 2）抗体-小分子缀合物形式的新型治疗先导物; 3）制备其他NaV亚型特异性抑制剂的蓝图。 公共卫生关系：阿片类镇痛剂，如吗啡，引起一系列副作用，并容易被滥用，但仍然是治疗疼痛最常用的处方药。我们希望开发新的药理学工具，通过干预特定的疼痛产生信号，以更深入地了解疼痛的病因。这些研究的结果可以帮助指导下一代疼痛管理疗法的开发。