RESUMO
Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Cicloparafinas/química , Integrinas/antagonistas & inibidores , Neoplasias/patologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Amidas/química , Compostos Aza/química , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Simulação por Computador , Ciclização , Humanos , Integrinas/metabolismo , Ligantes , Modelos Moleculares , Estrutura Molecular , Neoplasias/metabolismo , Peptídeos Cíclicos/química , Sensibilidade e EspecificidadeRESUMO
The α(v)ß(3) integrin is an adhesion molecule involved in physiological and pathological angiogenesis as well as in tumor invasion and metastasis, and therefore, there is a strong interest in developing novel agents interacting with this molecule. We report the synthesis and characterization of fluorescent α(v)ß(3) integrin probes and their use to visualize integrin α(v)ß(3) expression on human normal and cancer cells. The fluorescent probes we describe here may be of use for noninvasive imaging of α(V)ß(3) integrin expression also in vivo.
Assuntos
Corantes Fluorescentes/química , Integrina alfaVbeta3/análise , Imagem Molecular/métodos , Peptídeos Cíclicos/química , Peptidomiméticos/química , Linhagem Celular Tumoral , Células Cultivadas , Células Endoteliais/metabolismo , Corantes Fluorescentes/análise , Corantes Fluorescentes/síntese química , Humanos , Integrina alfaVbeta3/metabolismo , Ligantes , Estrutura Molecular , Peptídeos Cíclicos/metabolismo , Peptidomiméticos/síntese química , EstereoisomerismoRESUMO
The specificity of SEL1L expression and promoter activity for the pancreatic cell population, its chromosomal location, as well as its similarities to the yeast Hrd3p protein, a component of HRD complex which is responsible for endoplasmic reticulum (ER)-associated degradation of numerous ER-resident proteins, prompted us to study its effects on beta cell function. In this study we show that lowering SEL1L expression, by using the short interfering RNAs technology as well as antisense transfection, resulted in severe perturbation of betaTC-3 growth and metabolic activity. We hypothesize that SEL1L may exert its function by protecting the cells from ER stress and could counteract immune responses.
