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，例如吗啡、氢吗啡酮和芬太尼，广泛用于治疗急性、术后和慢性疼痛。尽管临床用途广泛，但许多副作用仍然存在，包括嗜睡、精神错乱、恶心、痛觉过敏和呼吸抑制。阿片类药物也很容易上瘾，并被 NIDA 视为滥用药物。我们希望开发新的药理学工具来探究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讯的完整膜蛋白。十个哺乳动物基因已被测序，编码十种不同的通道亚型（NaV1.1-1.9 和 NaX），每种亚型都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）可用作短效局部麻醉剂，但对于任何类型的全身或长期使用都不太理想。然而，大量令人信服的证据表明，对单一 NaV 同工型的特异性抑制可以降低疼痛敏感性，而不会产生与局部麻醉治疗相关的副作用（麻木、共济失调）（并且不会像阿片类药物那样导致成瘾）。九种 NaV 异构体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部分努力。我们的方法将利用单克隆抗体的高度特异性结合，该单克隆抗体被设计用于靶向单一 NaV 同工型。我们设想利用针对 NaV1.7 的抗体作为疼痛治疗的靶标，NaV1.7 是一种特别令人感兴趣的通道亚型。通过与该抗体共价连接一种有效的小分子通道拮抗剂，可以抑制离子传导。石房蛤毒素是一种低分子量的天然产物，通过沉积在通道孔的外口，对 NaV1.1-1.4、1.6 和 1.7 产生纳摩尔效力。将制定策略将修饰形式的 (+)-石房蛤毒素与抗体缀合，并测试这些药物作为 NaV 功能异构体特异性阻断剂的功效。该计划的成功将提供：1）可用于验证 NaV1.7 作为疼痛治疗靶标的工具； 2) 抗体-小分子缀合物形式的新型治疗先导药物； 3) 制备其他 NaV 异构体的特异性抑制剂的蓝图。 公共卫生相关性：吗啡等阿片类镇痛药会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来发挥作用，以便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。