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）：广泛规定了阿片类镇痛药，例如吗啡，氢球和芬太尼，用于治疗急性，术后和慢性疼痛。尽管这种广泛的临床用途，但许多副作用持续存在，包括嗜睡，混乱，恶心，痛觉过敏和呼吸道抑郁症。阿片类药物也令人上瘾，并被NIDA被视为滥用药物。我们希望开发新的药理学工具，以审查特定的生化机制，这些机制是疼痛感的基础，其长期目标是揭示下一代治疗疼痛治疗。电压门控的Na+离子通道是负责细胞之间电通通信的整体膜蛋白。已经对十个哺乳动物基因进行了测序，该基因编码了十个不同的同工型（NAV1.1-1.9和NAX），每个同工型具有独特的生物物理特征，以及细胞和组织分布模式。抑制非特异性NAV的药物（例如，利多卡因）发现应用是短持久的局部麻醉药，但对于任何类型的系统性或慢性使用而言，它都不可取。然而，令人信服的证据表明，对单个NAV同工型的特定抑制可以降低疼痛敏感性，而无需与局部麻醉治疗相关的伴随副作用（麻木，共济失调）（如阿片类药物所述，没有成瘾的机会）。九种NAV同工型的大分子结构中的相似性挫败了大多数努力，以开发仅作为单个通道亚型的拮抗剂的药物。我们的方法将利用该抗体的高度特异性结合，该抗体旨在靶向单个NAV同工型。我们设想利用针对NAV1.7的抗体，这是一种特别感兴趣的同工型，作为疼痛治疗的靶标。离子传导将通过共价链接到该抗体一种有效的小分子通道拮抗剂来抑制。萨克西毒素是一种低分子量，天然存在的产物，通过在通道孔的外口储藏在NAV1.1.1.4、1.6和1.7上以纳摩尔效力作用。将制定策略，以将（+） - saxitoxin的修改形式结合到抗体中，并测试这些试剂作为NAV功能的同工型特异性阻滞剂的功效。该程序的成功将提供：1）可用于验证NAV1.7作为疼痛治疗的目标的工具； 2）一种新型的治疗铅，形式为抗体 - 小分子结合； 3）用于制备其他NAV同工型的特定抑制剂的蓝图。 公共卫生相关性：阿片类镇痛药，例如吗啡，会导致一系列副作用并受到滥用，但仍然是最常开处方的药物来治疗疼痛。我们希望开发新的药理学工具，通过干预特定的产生疼痛的信号，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发展。