RESUMEN
Dimeric peptide-based inhibitors of postsynaptic density-95 (PSD-95) can reduce ischemic brain damage and inflammatory pain in rodents. To modify the pharmacokinetic profile, we designed a series of fatty acid linked dimeric ligands, which potently inhibits PSD-95 and shows improved in vitro blood plasma stability. Subcutaneous administration in rats showed extended stability and sustained release of these ligands. This can facilitate new pharmacological uses of PSD-95 inhibitors and further exploration of PSD-95 as a drug target.
Asunto(s)
Diseño de Fármacos , Ácidos Grasos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Péptidos/química , Animales , Homólogo 4 de la Proteína Discs Large , Relación Dosis-Respuesta a Droga , Ácidos Grasos/síntesis química , Ácidos Grasos/química , Ligandos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Peptide YY (PYY) is a gut hormone that activates the G protein-coupled neuropeptide Y (NPY) receptors, and because of its appetite reducing actions, it is evaluated as an antiobesity drug candidate. The C-terminal tail of PYY is crucial for activation of the NPY receptors. Here, we describe the design and preparation of a series of PYY(3-36) depsipeptide analogues, in which backbone amide-to-ester modifications were systematically introduced in the C-terminal. Functional NPY receptor assays and circular dichroism revealed that the ψ(CONH) bonds at positions 30-31 and 33-34 are particularly important for receptor interaction and that the latter is implicated in Y2 receptor selectivity.