# Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

> **NIH NIH R56** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $470,533

## Abstract

Abstract
 The Galbulimima (GB) alkaloids are derived from the bark of the Galbulimima genus,
which features in the traditional medicine and ritual of Papua New Guinea. The number of
alkaloids contained in the bark and their general scarcity, combined with the number of proteins
defined by the average neuron transcriptome, complicate identification of the highest potency
biomolecular targets associated with each physiologic response. Here we delineate a novel,
unifying hypothesis for the likely biological targets of the Galbulimima alkaloids and a new
chemical platform for its experimental interrogation. The mechanistic hypothesis is supported by
extensive preliminary data including the first new biological target identified in over three
decades. The synthetic platform is supported by syntheses that reduce synthetic burden
approximately three-fold.
 The first section of the grant demonstrates a new strategy for GB alkaloid accession by
conversion of high fraction aromatic (FAr) scaffolds to high fraction sp3 (Fsp3), stereochemically-
rich natural products. New cross-coupling reactions assemble aromatic feedstocks efficiently;
we propose asymmetric variants to render existing racemic routes enantioselective. Importantly,
existing and proposed routes are highly divergent and allow exploration of how structural
variation correlates to selectivity among a superfamily of receptors that likely confer the activity
of the GB alkaloids.
 The second section of the grant relies on a novel mechanistic hypothesis for the function
of the Galbulimima alkaloids. The synthetic platform outlined here combined with advances in
robust cell-based second messenger assays now widely available for the receptor family of
interest allow unprecedented ability to probe structure, function and selectivity of the GB
alkaloids. Alternative strategies for target identification using photo-crosslinking and thermal
proteome profiling will be pursued if a high affinity target within existing assays cannot be found.
Ultimately, we expect to identify enough ligand-receptor pairs to begin building a GB alkaloid-
receptor interactome to map structure-function relationships independent of and complementary
to high resolution binding models. This research holds great potential to identify privileged new
scaffold leads for therapeutic development from plant metabolites already validated in humans.

## Key facts

- **NIH application ID:** 10695398
- **Project number:** 1R56AT012075-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Ryan Ashok Shenvi
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $470,533
- **Award type:** 1
- **Project period:** 2022-09-26 → 2023-06-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695398

## Citation

> US National Institutes of Health, RePORTER application 10695398, Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment (1R56AT012075-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10695398. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*