RESUMO
C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B), are potent positive regulators of endochondral bone growth, making the CNP pathway one of the most promising therapeutic targets for the treatment of growth failure. However, the administration of exogenous CNP is not fully effective, due to its rapid clearance in vivo. Modification of CNP to potentially druggable derivatives may result in increased resistance to proteolytic degradation, longer plasma half-life (T1/2), and better distribution to target tissues. In the present study, we designed and evaluated CNP/ghrelin chimeric peptides as novel CNP derivatives. We have previously reported that the ghrelin C-terminus increases peptide metabolic stability. Therefore, we combined the 17-membered, internal disulfide ring portion of CNP with the C-terminal portion of ghrelin. The resultant peptide displayed improved biokinetics compared to CNP, with increased metabolic stability and longer plasma T1/2. Repeated subcutaneous administration of the chimeric peptide to mice resulted in a significant acceleration in longitudinal growth, whereas CNP(1-22) did not. These results suggest that the ghrelin C-terminus improves the stability of CNP, and the chimeric peptide may be useful as a novel therapeutic agent for growth failure and short stature.
Assuntos
Grelina , Natriuréticos , Peptídeo Natriurético Tipo C , Sequência de Aminoácidos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Grelina/administração & dosagem , Grelina/química , Grelina/farmacocinética , Grelina/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Natriuréticos/administração & dosagem , Natriuréticos/química , Natriuréticos/farmacocinética , Natriuréticos/farmacologia , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/farmacocinética , Peptídeo Natriurético Tipo C/farmacologia , Osteogênese/efeitos dos fármacos , Estabilidade Proteica , Proteólise , Ratos , Ratos Sprague-DawleyRESUMO
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073µM, indicating 350-fold potency compared to the hit compound 3.