# Synthetic biology to discover kratom natural product biosynthetic pathways for biased analgesic development

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $427,412

## Abstract

Project Summary
 Opioid alternative analgesics that would kill pain potently without the respiratory side effect will be of
specific importance in addressing the opioid crisis. The medicinal herb kratom (Mitragyna speciosa) produces
natural products (mitragynine and 7-hydroxymitragynine) that selectively activate analgesia only, which are
promising “biased” opioid alternatives. Elucidating the kratom biosynthetic pathway composed of enzymes
catalyzing sequential reactions toward the syntheses of mitragynine, 7-hydroxymitragynine, or other kratom
products is important to the development of “biased” non-opioid analgesics. We propose to identify and
reconstruct both the kratom biosynthetic pathways and the plant enzyme complexes organizing plant
biosynthesis in yeast by integrating plant functional genomics analysis and synthetic biology. The research will
provide new chemical and plant biology knowledge to a broader community, develop a post-translational level
understanding of plant pathway regulation in yeast, and highlight the possibility of using synthetic biology to
understand how nature achieves complicated natural product biosynthesis.
 This proposal will develop the conceptual framework to understand how nature organizes the specialized
metabolism in plant toward high efficiency and complexity. The development of high-throughput protein-protein
interaction method in yeast for plant complex identification will provide new methods and knowledge for plant
pathway discovery and reconstruction. The methods and knowledge we develop toward these goals will also
enable the structural elucidation, biological activity evaluation, and microbial production of biased opioid
alternatives, leading to the development of next-generation painkillers to address the opioid crisis.

## Key facts

- **NIH application ID:** 10981335
- **Project number:** 1R01AT012633-01A1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** SIJIN LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,412
- **Award type:** 1
- **Project period:** 2024-06-06 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981335

## Citation

> US National Institutes of Health, RePORTER application 10981335, Synthetic biology to discover kratom natural product biosynthetic pathways for biased analgesic development (1R01AT012633-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981335. Licensed CC0.

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