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.