Tuesday, November 28, 2023
11/28/2023
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.
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