Synthetic Scavenger Medical Countermeasures for Fentanyl

芬太尼的合成清除剂医疗对策

• 批准号: 10726539
• 负责人: Michal Avital-Shmilovici
• 金额: $ 37.03万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726539
• 关键词: Agonist; Antibodies; Antidotes; Asialoglycoprotein Receptor; Binding; Biological; Biological Assay; Blood; Butyrylcholinesterase; Canada; Cell Line; Cells; Cellular Assay; Characteristics; Chemical Weapons; Classification; Clinical; Cocaine; Complex; Country; Data; Development; Disadvantaged; Dose; Drug Kinetics; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemic; Evaluation; Exhibits; Fentanyl; Fiber Optics; Future; Half-Life; Heroin; Hour; Human; Hydrocortisone; In Vitro; Interferometry; Interleukin 6 Receptor; Interleukin-6; Intramuscular Injections; Iran; Kinetics; Lead; Libraries; Mammalian Cell; Molecular Weight; Monoclonal Antibodies; Morphine; Mus; Naloxone; Opioid; Opioid Antagonist; Opioid agonist; Organophosphates; Outcome; Overdose; Pharmacologic Substance; Precipitation; Property; Prophylactic treatment; Proteins; Public Health; Publishing; Rapid screening; Rattus; Reporting; Research; Research Project Grants; Risk; Russia; SARS-CoV-2 B.1.1.7; Scanning; Site; Structure; Substance Withdrawal Syndrome; Supplementation; Symptoms; TNF gene; Technology; Testing; Toxic effect; Translations; United States; Ventilatory Depression; absorption; antagonist; bioscavenger; carfentanil; combat; combinatorial; coping; design; drug discovery; experimental study; fentanyl overdose; fentanyl use; follow-up; immunogenicity; improved; inhibitor; innovation; innovative technologies; intravenous administration; medical countermeasure; member; mouse model; mu opioid receptors; nerve agent; new technology; novel; novel therapeutics; opioid abuse; opioid mortality; opioid overdose; opioid withdrawal; optical fiber; organophosphate poisoning; overdose death; pharmacokinetic characteristic; pharmacologic; preclinical efficacy; prevent; programs; protein protein interaction; receptor; receptor binding; screening; small molecule; success; symposium; synthetic opioid; tool

PROJECT SUMMARY/ABSTRACT Opioid abuse has become a growing epidemic in the US, causing tens of thousands of overdose deaths every year especially because of fentanyl-related opioids. Fentanyl is a synthetic opioid that acts as an agonist on the μ-opioid receptors at various sites and is estimated to be 100 times more potent than morphine. This has led to the classification of potent synthetic opioids as Pharmaceutical Based Agents (PBAs) that could be used as a potential offensive chemical weapon, indicating the critical need for effective medical countermeasures (MCMs). Naloxone is a non-selective competitive opioid receptor antagonist that is given to reverse the symptoms of opioid overdose or toxicity. It is highly effective, but also has several disadvantages. For example, it has low efficacy against potent opioids like fentanyl and can require multiple doses to avoid renarcotization, but may then precipitate opioid-withdrawal syndrome. Bioscavengers are an attractive MCM strategy for both post-exposure therapy and prophylaxis against toxic agents such as organophosphate nerve agents. Recently, monoclonal antibodies (mAbs) were shown in mice to be fentanyl and carfentanil bioscavengers, and to reduce blood opioid concentrations. However, since a stoichiometric bioscavenger is needed to neutralize the fentanyl molecules, and since mAbs are large (~150 kDa), the dose of the mAbs required for protection from or treatment of opioid toxicity is large and difficult to administer. Therefore, an urgent need exists for new MCMs that can be used in conjunction with receptor antagonists like naloxone to overcome the limitations of current treatments. This exploratory research program seeks to develop synthetic scavengers for fentanyl for opioid overdose and toxicity reversal utilizing SRI’s proprietary Fiber-optic Array Screening Technology (FAST) and protein-like synthetic molecules (Techneins). We developed this platform to enable the design, synthesis, screening and sequencing of large combinatorial “one-bead one-compound” Technein libraries. FAST enables screening against multiple targets in complex biological matrices to yield lead compounds with specific biological functionality and high selectivity. This approach has been validated as a drug discovery tool for inhibitors of protein-protein interactions and for small molecule binders. In preliminary studies, when a small portion of a library was screened against fentanyl, several Technein hits were identified and confirmed to bind. Their relatively small size (4-6 kDa), high stability, lack of immunogenicity and a good terminal half-life (~22 hours), make Techneins ideal candidates as opioid scavengers. Here we aim to develop synthetic scavenger Techneins for fentanyl and test and optimize their ability to block fentanyl activity in functional cellular assays (Aim 1) and provide basic PK and pre-clinical efficacy data for the top anti-fentanyl lead (Aim 2). These studies will enable new avenues for the development of efficacious MCMs against fentanyl and related synthetic opioids, as well as paving the way for coping with other types of toxic agents. Moreover, the project may further demonstrate utility of an innovative new drug discovery platform.

项目摘要/摘要 阿片类药物滥用已成为美国日益增长的流行病，每次造成数以万计的过量死亡 一年，特别是因为芬太尼相关的阿片类药物。芬太尼是一种合成的阿片类药物，充当激动剂 各个部位的μ阿片受体，估计是吗啡的100倍。这导致了 将潜在合成阿片类药物分类为基于药物的剂（PBA），可以用作 潜在的进攻性化学武器，表明对有效医疗对策（MCM）至关重要。 纳洛酮是一种非选择性竞争性阿片类药物受体拮抗剂，可扭转 阿片类药物过量或毒性。它非常有效，但也有几个缺点。例如，它的低 针对芬太尼等潜在阿片类药物的效率，并且可能需要多剂以避免重骨化，但可能会 沉淀的阿片类抽水综合征。 BioScavengers是两种暴露后的有吸引力的MCM策略 治疗和预防毒性药物，例如有机磷酸盐神经剂。最近，单克隆 在小鼠中显示抗体（mAb）为芬太尼和carfentanil bioscavengers，并减少血液阿片类药物 浓度。但是，由于需要一个化学计量的生物载体来中和芬太尼分子，所以 并且由于mAb较大（〜150 kDa），因此保护或处理OOID所需的mAb剂量 毒性很大且难以给药。因此，迫切需要用于新的MCMS 与纳洛酮等受体拮抗剂的结合以克服当前治疗的局限性。 该探索性研究计划旨在开发用于阿片类药物过量和的芬太尼的合成清除剂 利用SRI专有光纤阵列筛选技术（快速）和类似蛋白质的毒性逆转 合成分子（Techneins）。我们开发了这个平台以实现设计，合成，筛选和 大型组合“单珠一体化合物” Technein库的测序。快速启用筛选 针对复杂生物学物质中的多个靶标，以产生具有特定生物学的铅化合物 功能和高选择性。该方法已被证实为用于抑制剂的药物发现工具 蛋白质蛋白相互作用和小分子粘合剂。在初步研究中，一小部分 对图书馆进行了筛选，针对芬太尼，确定了几个Technein命中并确认绑定。他们的 相对较小的尺寸（4-6 kDa），高稳定性，缺乏免疫原性和良好的末端半衰期（约22小时）， 使Techneins成为阿片类药物清除剂的理想候选者。 在这里，我们旨在开发芬太尼的合成清道夫techneins，并测试并优化其阻止的能力 功能性细胞测定中的芬太尼活性（AIM 1），并为临床前的PK和临床前效率数据提供 顶部抗芬太尼铅（AIM 2）。这些研究将为开发有效的MCMS提供新的途径 针对芬太尼和相关的合成阿片类药物，并粘贴与其他类型的有毒的方法 代理商。此外，该项目可能进一步证明了创新的新药发现平台的实用性。