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.