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: 10386083
• 负责人: Natalia Harris
• 金额: $ 3.89万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386083
• 关键词: Affect; Agonist; Alkaloids; American; Anabolism; Analgesics; Attention; Binding; Biochemical; Biochemistry; Clinical Research; Constipation; Cyclization; Dehydration; Dependence; 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; 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; Pharmacology; 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; base; 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; reconstitution; response; scaffold; side effect; small molecule; stereochemistry; strictosidine

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.

提案摘要 Kratom（Mitragyna Speciosa）是一家在东南亚使用了数百年的医疗厂 自我治疗的慢性生气，阿片类药物和抑郁症。由于这些独特的药物效应 过去十年的Kratom在美国荧光，许多用户自我治疗的阿片类药物使用障碍和疼痛 管理。这种医用草药已成为许多人用来摆脱成瘾坑的生命生命， 而不是不断落入复发的陷阱。尽管最近引起了人们的关注，但这种植物仍然存在 在食品和药物管理局和由于 有限或初步临床研究。虽然，已经对Kratom的主要研究进行了一些研究 生物碱MITragynine，表征它是通过G蛋白激活的μ阿片受体的部分拮抗剂 信号级联。 kratom用户报告可减轻疼痛的特性和负面副作用的部署，例如 与基于吗啡的阿片类药物相比，便秘，成瘾和呼吸道抑郁症。此外，研究 表明某些Mitragynine类似物，例如mitragynine pseudondoxyl和7-羟基甲基氨酸，甚至是 µ-阿片受体的更多潜在激动剂，尽管这些受体的完整结构活动关系 生物碱尚未建立。那就是关于操纵何处以及如何操纵的未解决问题 Mitragynine是最终的阿片类药物替代药。我们的目标是完全阐明 MITRAGYNINE确定产生Mitragynine支架所需的生物催化转化。 确定生物催化途径打开了操纵临界催化剂的大门，形成mitragynine至 产生类似物，可以增强这种独特的生物碱已显示的药物特性。 此外，我们计划通过表征和工程柔性催化剂来进一步衍生Mitragynine 从其他生物体产生具有替代环化，立体化学或功能的Mitragynine类似物 小组模式。通过这项研究，我们将生成一个Mitragynine类似物库，目的是确定 有效治疗阿片类药物使用障碍的有效候选人。推翻的假设是通过 蛋白质工程我们可以将mitragynine支架多样 方法并制备具有增强的药物特性的新型化合物 回复。最终，Mitragynine类似物有可能快速发展新的和更安全的发展 因此，阿片类药物使用障碍的治疗方法永久改善了受影响者的生活。