Friday, July 26, 2024
7/26/2024
ABSTRACT Substance abuse disorder (SUD) is a chronic devastating disease with significant socio-economic burden. Because SUD currently lacks targeted therapeutics there is an urgent need to identify new molecular targets for medication development. Here, we have identified the fibroblast growth factor 13 (FGF13), an accessory protein of the voltage-gated Nav channel and a fine-tune regulator of neuronal excitability, as a novel target relevant for cocaine addiction in the nucleus accumbens shell (NAc shell). Supporting studies predict low level of FGF13 mRNA as protective against cocaine addiction. Thus, limiting the interaction between FGF13 and the Nav channel could lead to novel therapeutics against cocaine addiction. Using a rational design approach, we have developed PM1, a peptidomimetic derived from four amino acids at the protein-protein interaction (PPI) interface between FGF13 and Nav1.6, the determinant of firing in medium firing neurons (MSNs) in the NAc shell. PM1 inhibits FGF13:Nav1.6 interaction and suppresses Nav1.6- mediated currents in an use-dependent manner, suggesting that in vivo PM1 or its derivatives might selectively inhibit hyper-excitability of MSNs which is a hallmark of early-phase of cocaine addiction. Building on these results, we have generated a collection of ~ 500 small molecules, PM1 derivatives, which we plan to screen using a validated platform of in vitro and in cell assays geared to hit selection for electrophysiology and behavioral studies in experimental models of cocaine addiction. Proof of concept data of preclinical selectivity, safety and efficacy we will generated using a combination of in vivo gene transfer for genetic validation of FGF13 and pharmacology of selected small molecules derived from PM1. Outcomes of this research could advance a new lead compound towards an investigational new drug (IND) application advancing the field of medication development against SUD.
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