Thursday, June 12, 2025
6/12/2025
Biosynthesis and biological mechanism of minor cannabinoids - Project Summary / Abstract This joint application by biosynthetic chemist Bradley Moore (UCSD/SIO) and neuroscientist Jerold Chun (SBP) is in response to the Notice of Special Interest: Promoting Mechanistic Research on Therapeutic and Other Biological Properties of Minor Cannabinoids and Terpenes recently issued by NCCIH (NOT-AT-22-027). The Moore and Chun laboratories have synergized their complimentary research efforts to address a mounting national health concern and opportunity surrounding the legalization and increased use of cannabis by millions of Americans both medicinally and recreationally. They aim to expand their new biocatalytic methods to construct rare and minor cannabinoids and analogs and to evaluate their potential therapeutic benefits in murine and human receptor assays and animal models. The successful development of new cannabinoid therapeutics depends on comprehensive pharmacological data, especially for the >110 minor phytocannabinoids. Given the paucity of functional information on them, the significance of the endocannabinoid system in the regulation and control of many critical bodily functions, and the relevant crosstalk between cannabinoid (CB) and lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR) systems, we hypothesize that phytocannabinoids and/or their metabolic derivatives similarly modulate non-classical LPA receptors. Our preliminary work indicates that CBC phosphate (CBCp) engages the receptor LPA1, thereby opening new vistas for phytocannabinoid GPCR receptor biology, physiology and pathophysiology. We will test the hypothesis that phytocannabinoids and/or their metabolites modulate non-classical LPA as well as classical CB receptors to impact physiology and disease through two specific aims over the next five years. Specific aim 1 will discover, characterize, and engineer biocatalysts for the construction of structurally diverse minor cannabinoids and analogues. We will expand our preliminary results that bacterial enzymes can be used to chemoenzymatically synthesize cannabinoid molecules. Biochemical, genetic, and engineering approaches using diverse enzyme and substrate libraries will expand our ability to produce diverse cannabinoid molecules for biological evaluation. Specific aim 2 will interrogate non-classical and classical cannabinoid receptor interactions through the use of backscattering interferometry and cell-based receptor assays; and animal studies using wildtype and receptor-knockout mice that will assess normal physiological effects and pathophysiological effects previously linked to LPA signaling, including neuropathic pain (partial sciatic nerve ligation (PSNL)) and multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)). These studies will reveal new insights into the minor cannabinoids and their cross-talk to lysophopholipids, which have genuine therapeutic potential.
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