Recovery is Achievable: Biocatalytic approaches to Diversifying Mitragynine Analogs for Opioid Substitution Therapies

康复是可以实现的：生物催化方法使帽柱木碱类似物多样化用于阿片类药物替代疗法

• 批准号: 10557089
• 负责人: Natalia Harris
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557089
• 关键词: Acceleration; Affect; Agonist; Alkaloids; American; Anabolism; Analgesics; Attention; Binding; Biochemical; Biochemistry; Clinical Research; Constipation; Cyclization; Dehydration; Dependence; Derivation procedure; Development; Disease Management; Engineering; Enzyme Tests; Enzymes; Exhibits; Eye; GTP-Binding Proteins; Generations; Genome; Goals; Homologous Gene; Hydroxylation; Indole Alkaloids; Libraries; Life; Mammals; Medicinal Herbs; Medicinal Plants; Medicine; Mental Depression; Methadone; Methods; Methylation; Mining; Mitragyna; Molecular; Monoterpenes; Morphine; Natural Products; Opiate Addiction; Opioid; Opioid Receptor; Opioid Rotation; Opioid agonist; Opioid replacement therapy; Organism; Pain management; Pathway interactions; Pattern; Pharmaceutical Preparations; Plant alkaloid; Plants; Production; Property; Protein Engineering; Reaction; Recovery; Relapse; Reporting; Research; Route; Signaling Protein; Southeastern Asia; Stimulant; Structure; Structure-Activity Relationship; Therapeutic; Trees; United States Food and Drug Administration; Ventilatory Depression; addiction; analog; antagonist; catalyst; chronic pain management; delta opioid receptor; design; drug discovery; enzyme pathway; experience; falls; flexibility; functional group; improved; mitragynine pseudoindoxyl; mu opioid receptors; non-Native; novel; opioid epidemic; opioid overdose; opioid use disorder; opioid withdrawal; overdose death; pain relief; pandemic disease; pharmacologic; reconstitution; response; scaffold; side effect; small molecule; stereochemistry; strictosidine; structural determinants

Proposal Summary Kratom (Mitragyna speciosa) is a medicinal plant that has been used in Southeast Asia for hundreds of years to self-treat chronic-pain, opioid with-drawl, and depression. Due to these unique pharmacological effects, in the past decade Kratom has flourished in the U.S. with many users self-treating opioid use disorder and pain management. This medicinal herb has become a life-raft many use to pull themselves out of the pit of addiction, rather than continuously falling in the trap of relapsing. Despite the recent attention, this plant remains controversial in the eyes of the Food and Drug Administration and the Drug Enforcement Administration due to limited or preliminary clinical research. Although, several studies have been conducted on Kratom’s primary alkaloid mitragynine, characterizing it a partial antagonist of the μ-opioid receptor activated through the G-protein signaling cascade. Kratom users report pain relieving properties and a depletion in negative side effects such as constipation, addiction, and respiratory depression compared to morphine-based opioids. Furthermore, studies show that some mitragynine analogs such as mitragynine pseudoindoxyl and 7-hydroxymitragynine are even more potent agonists of the µ-opioid receptor, although a complete structure activity relationship of these alkaloids has not been established. Thus, unanswered questions remain regarding where and how to manipulate mitragynine to be the ultimate opioid substitution drug. Our goal is to fully elucidate the biosynthetic pathway of mitragynine to determine the biocatalytic transformations required to produce the mitragynine scaffold. Determining the biocatalytic pathway opens the door to manipulate critical catalysts that form mitragynine to produce analogs that may enhance the pharmacological properties already displayed from this unique alkaloid. Furthermore, we plan to derivatize mitragynine even further by characterizing and engineering flexible catalysts from other organisms to produce mitragynine analogs with alternative cyclization, stereochemistry or functional group patterns. Through this study we will generate a library of mitragynine analogs with the goal of identifying effective candidates to help treat opioid use disorder. The overreaching hypothesis is that through methods of protein engineering we can diversify the mitragynine scaffold beyond what is attainable through general synthetic approaches and prepare novel compounds with enhanced pharmacological properties concerning opioid response. Ultimately, mitragynine analogs have the potential to fast-track the development of new and safer treatments for opioid use disorders therefore permanently improving the lives of those affected.

建议书摘要 KrATOM是一种药用植物，在东南亚已有数百年的历史 自我治疗慢性疼痛、阿片类药物和抑郁症。由于这些独特的药理作用，在 在过去的十年里，Kratom在美国蓬勃发展，许多使用者自我治疗阿片类药物使用障碍和疼痛 管理层。这种草药已经成为许多人用来摆脱毒瘾的救生艇， 而不是不断陷入故态复萌的陷阱。尽管最近受到了关注，但这种植物仍然 食品药品监督管理局和药品监督管理局眼中有争议的原因 有限的或初步的临床研究。尽管，已经对Kratom的初选进行了几项研究 生物碱米曲宁，其特征是通过G蛋白激活的μ阿片受体的部分拮抗剂 信号级联。KrATOM用户报告疼痛缓解特性和负面副作用的耗尽，如 与基于吗啡的阿片类药物相比，便秘、成瘾和呼吸抑制。此外，研究 证明了一些三氮杂环丙氨酸类似物，如三氮杂环丙氨酸、伪吲哚和7-羟基三氮杂环丙氨酸是偶数的 更有效的阿片受体激动剂，尽管这些激动剂具有完整的构效关系 生物碱还没有被确定。因此，关于在哪里以及如何操纵仍然存在悬而未决的问题 米拉吉宁有望成为最终的阿片类替代药物。我们的目标是充分阐明生物合成途径。 确定生产米曲宁支架所需的生物催化转化。 确定生物催化途径打开了操纵关键催化剂的大门，这些催化剂形成丝裂原碱以 生产类似物，可以增强这种独特的生物碱已经显示出的药理特性。 此外，我们计划通过表征和设计灵活的催化剂来进一步衍生米曲金宁。 从其他生物中分离出来，以环化、立体化学或官能化的交替方式产生米曲宁类似物 群体模式。通过这项研究，我们将建立一个米托吗类似物的文库，目标是确定 帮助治疗阿片类药物使用障碍的有效候选人。过分的假设是，通过 通过蛋白质工程，我们可以使米特拉宁支架多样化，而不是通过一般的合成 阿片类药物药理活性增强新化合物的制备 回应。最终，米曲宁类似物有可能快速开发出新的更安全的药物 治疗阿片类药物使用障碍，从而永久性地改善受影响者的生活。