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

提案摘要 Kratom（Mitragyna speciosa）是一种药用植物，已在东南亚使用了数百年， 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， 过去十年Kratom在美国蓬勃发展.许多用户自我治疗阿片类药物使用障碍和疼痛 管理这种草药已经成为许多人用来把自己从上瘾的深渊中拉出来的救生筏， 而不是不断地落入复发的陷阱。尽管最近受到关注，但这种植物仍然 由于美国食品和药物管理局和缉毒局的原因， 有限或初步临床研究。虽然，几项研究已经进行了Kratom的主要 生物碱mitragynine，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用户报告疼痛缓解属性和负面副作用，如消耗 便秘，成瘾和呼吸抑制与吗啡类阿片类药物相比。此外，研究 显示了一些mitragynine类似物如mitragynine假吲哚和7-羟基mitragynine甚至 更有效的μ-阿片受体激动剂，尽管这些化合物的完整结构活性关系 生物碱尚未建立。因此，关于在何处以及如何操纵 mitragynine是最终的阿片类药物替代品。我们的目标是充分阐明的生物合成途径 用mitragynine测定产生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形成mitragynine的关键催化剂的大门， 产生类似物，可以增强这种独特生物碱已经显示的药理学特性。 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Mitragynine 从其它生物体中分离得到具有交替环化、立体化学或功能性的mitragynine类似物， 群体模式通过这项研究，我们将产生一个图书馆的mitragynine类似物的目标是确定 有效的候选人，以帮助治疗阿片类药物使用障碍。过度假设是，通过 蛋白质工程，我们可以多样化的mitragynine支架超出了通过一般合成 方法和制备具有增强的关于阿片样物质的药理学性质的新化合物 反应最终，mitragynine类似物有可能快速开发新的和更安全的药物。 因此，对类阿片使用障碍的治疗永久地改善了受影响者的生活。

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.