Developing high-precision epigenetic therapeutics for opioid use disorder

Abstract Opioid abuse disorder (OUD) is a growing epidemic that disrupts numerous lives and local communities in the United States. No effective therapeutics exist to counter the addiction; current OUD therapeutics such as methadone, buprenorphine, and naltrexone are opioid mimetics, either exerting weaker potency or blocking the opioids from binding with their cognate receptors. Epigenetic modifications on histone marks play key causative roles in mediating opioid addiction. Such epigenetic modifications generate “persisting impacts” on the reward circuitry of the brain by altering chromatin structure and synaptic rewiring. Unfortunately, current epigenetic drugs are not suitable for drug addiction therapeutics. The fundamental problem is that epigenetic regulators play numerous roles in different tissues and under diverse cellular contexts; thus, enzyme-inhibitory epigenetic drugs tend to cause very high off-target toxicities that are unacceptable outside of oncological indications. Recently, we developed a novel approach that identified high-precision small-molecules by targeting protein-protein interactions (PPI) of an epigenetic protein complex involving histone deacetylase (HDAC). In particular, we demonstrated a SIN3-binding molecule that disrupts the HDAC SIN3 complex recruitment to chromosomal loci. This molecule could block LSD-induced hallucination as effectively as a genetic HDAC2 knockout in the mouse prefrontal cortex, while only minimally inducing off-target gene expression. By adapting this approach, we seek to develop high-precision PPI-targeting molecules for OUD. The neuronal G9a complex is an attractive target regulating ΔFosB expression under chronic opioid exposure. We will apply a mammalian cell-based compound screening platform to identify functional modulators of the G9a complex and biophysically characterize their drug-protein interactions. The efficacy and specificity of the final hits will be tested in OUD animal models where behavioral responses and biomarkers in the brain will be examined. We aim for our work to result in an effective, epigenetically targeting OUD therapeutic that helps individuals impacted by this condition to recover safely.