RESUMEN
Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-effects and many have entered the clinic as type 2 diabetes and obesity therapeutics. In this work, we describe strategies for improving the stability of the peptide ligands by making them refractory to dipeptidyl peptidase-4 catalyzed hydrolysis and inactivation. We describe a series of alkylations with variations in size, shape, charge, polarity, and stereochemistry that are able to engender full activity at the receptor(s) while simultaneously resisting enzyme-mediated degradation. Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence.
Asunto(s)
Péptido 1 Similar al Glucagón , Humanos , Péptido 1 Similar al Glucagón/química , Péptido 1 Similar al Glucagón/metabolismo , Diseño de Fármacos , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptidos/química , Polipéptido Inhibidor Gástrico/química , Polipéptido Inhibidor Gástrico/metabolismo , Alquilación , Glucagón/química , Glucagón/metabolismo , Animales , Ligandos , Hidrólisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMEN
Cancer treatment is one of the major challenges facing the modern biomedical profession. Development of new small-molecule chemotherapeutics requires an understanding of the mechanism of action for these treatments, as well as the structure-activity relationship. Study of the well-known DNA-intercalating agent, doxorubicin, and its aglycone, doxorubicinone, was undertaken using a variety of spectroscopic and calorimetric techniques. It was found that, despite conservation of the planar, aromatic portion of doxorubicin, the agylcone does not intercalate; it instead likely binds to the DNA minor-groove.