Engineering systemically bioavailable analogs of endogenous neuropeptides

A significant amount of effort has been put into the research and development of peptide-based drugs for the treatment of human disease. The use of anticonvulsant neuropeptides for the treatment of pain and epilepsy has recently shown promise. Neuropeptides such as galanin (Gal), neuropeptide Y (NPY), neurotensin (NT), and neuropeptide W (NPW) modulate their biological activities through their respective receptor targets in the brain. Introduced intracerebroventricularly, these compounds have been shown to reduce pain and seizure activity. Upon systemic administration, however, these compounds do not exhibit the same potency. The metabolic instability and inability to penetrate the blood-brain barrier (BBB) has precluded their widespread use as drugs for neurological disorders. This work will describe the application of the lipidizationcationization strategy to several endogenous neuropeptides towards increasing their metabolic stability and improving systemic bioavailability. Based on existing structure activity relationship (SAR) information, analogs of Gal, NPY NT, and NPW were designed and chemically synthesized. The combination of increased cationic character (oligo-Lys motifs) and increased lipophilicity (lipoamino acid) resulted in analogs with increased octanol-water partitioning coefficients (logD), significantly improved metabolic stabilities, while retaining high affinities for their native receptors. Furthermore, these analogs were shown to modulate seizure activity in animal models of epilepsy upon systemic administration. Our results suggest that the cationizationlipidization strategy may be broadly applicable across a wide variety of neuropeptides, opening up a large repertoire of new drug candidates for the treatment of neurological disorders.