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

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $38,937

## Abstract

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.

## Key facts

- **NIH application ID:** 10386083
- **Project number:** 1F31DA055451-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Natalia Harris
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,937
- **Award type:** 1
- **Project period:** 2022-02-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386083

## Citation

> US National Institutes of Health, RePORTER application 10386083, Recovery is Achievable: Biocatalytic approaches to Diversifying Mitragynine Analogs for Opioid Substitution Therapies (1F31DA055451-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386083. Licensed CC0.

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