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

基本信息

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
项目类别：
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

项目摘要

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。由于这些独特的药理作用，可以自我治疗慢性疼痛、阿片类药物戒断和抑郁症。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这种药草已成为许多人用来摆脱毒瘾深渊的救生筏，尽管最近受到关注，但这种植物仍然存在，而不是不断陷入复发的陷阱。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尽管如此，已经对卡痛的主要成分进行了几项研究。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卡痛叶使用者报告具有缓解疼痛的特性，并减少了负面副作用，例如此外，研究还发现，与基于吗啡的阿片类药物相比，它会导致便秘、成瘾和呼吸抑制。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-阿片受体的更有效的激动剂，尽管这些药物的完整结构活性关系因此，关于在哪里以及如何操纵的问题仍然没有得到解答。我们的目标是充分阐明帽柱木碱的生物合成途径。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通过这项研究，我们将生成一个帽柱木碱类似物库，目的是识别出帽柱木碱类似物。帮助治疗阿片类药物使用障碍的有效候选药物是通过以下方法。通过蛋白质工程，我们可以使帽柱木碱支架多样化，超出通过一般合成所能实现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。