RESUMO
[structure: see text]. A small library of cyclic RGD pseudopentapeptides incorporating stereoisomeric 6,5- and 7,5-fused bicyclic lactams was synthesized with the aim of developing active and selective integrin antagonists. The solid-phase synthesis and activity of these RGD derivatives is described. The approach led to two of the most active known inhibitors of alpha(V)beta3 receptor.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Lactamas/síntese química , Oligopeptídeos/síntese química , Receptores de Vitronectina/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/metabolismo , Ciclização , Peptídeos e Proteínas de Sinalização Intercelular , Cinética , Lactamas/química , Lactamas/metabolismo , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Biblioteca de Peptídeos , Peptídeos/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , Estrutura Secundária de Proteína , Ensaio Radioligante , Receptores de Vitronectina/químicaRESUMO
GITR is a type I transmembrane protein that belongs to the tumor necrosis factor/nerve growth factor receptor (TNF/NGFR) family. This receptor is preferentially expressed in activated T lymphocytes and may function as signaling molecule during T-cell development. In the present study, we examined the genomic organization of the entire mouse GITR (mGITR) gene. The gene spans a 2543-bp region and consists of five exons (with a length ranging from 88 bp to 395 bp) and four introns (67 bp to 778 bp). In agreement with GITR expression in activated T cells, consensus elements for transcription factors involved in T-cell development and activation were identified in the 5' flanking region, including a consensus element for NF-kappaB. Two highly significant binding sites for MyoD and one binding site for myogenin were also found, suggesting involvement of GITR in muscle development. The mGITR gene contains 17 transcription initiation sites distributed over a 76-bp region, all used with the same frequency. We localized mGITR to the murine chromosome 4 (E region), where other 4 TNF/NGFR members localize, including m4-1BB and mOX40. These results further indicate that GITR shares several features with OX40, 4-1BB, and CD27, suggesting the existence of a new subfamily of the TNFR family, as also confirmed by the similarity of their cytoplasmic domains.