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 卡痛叶（Mitragyna speciosa）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、阿片类药物戒断和抑郁症。由于这些独特的药理作用， 过去十年，卡痛在美国蓬勃发展，许多用户自行治疗阿片类药物使用障碍和疼痛 管理。这种药草已成为许多人用来摆脱毒瘾深渊的救生筏， 而不是不断陷入旧病复发的陷阱。尽管最近受到关注，这种植物仍然 由于以下原因，食品药品监督管理局和缉毒局认为存在争议 有限或初步的临床研究。尽管如此，已经对卡痛的主要成分进行了多项研究 生物碱帽柱木碱，其特征在于它是通过 G 蛋白激活的 μ-阿片受体的部分拮抗剂 信号级联。卡痛叶使用者表示，卡痛具有缓解疼痛的功效，并减少了负面副作用，例如 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 表明一些帽柱木碱类似物，例如帽柱木碱假吲哚酚和7-羟基帽柱木碱，甚至是 µ-阿片受体的更有效激动剂，尽管这些药物的完整结构活性关系 生物碱尚未确定。因此，关于在哪里以及如何操纵的问题仍然悬而未决。 帽柱木碱成为最终的阿片类药物替代药物。我们的目标是充分阐明其生物合成途径 帽柱木碱以确定生产帽柱木碱支架所需的生物催化转化。 确定生物催化途径为操纵形成帽柱木碱的关键催化剂打开了大门 产生的类似物可以增强这种独特生物碱已经表现出的药理学特性。 此外，我们计划通过表征和设计柔性催化剂进一步衍生帽柱木碱 从其他生物体中生产具有替代环化、立体化学或功能性的帽柱木碱类似物 组模式。通过这项研究，我们将建立一个帽柱木碱类似物库，目的是识别 帮助治疗阿片类药物使用障碍的有效候选人。过度的假设是通过以下方法 通过蛋白质工程，我们可以使帽柱木碱支架多样化，超出一般合成所能达到的范围 方法并制备具有增强的阿片类药物药理特性的新型化合物 回复。最终，帽柱木碱类似物有潜力快速开发新的、更安全的药物 因此，阿片类药物使用障碍的治疗可以永久改善受影响者的生活。