RESUMO
The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvß3 without cross reacting with αvß5 and αIIbß3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvß3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions.
Assuntos
Integrina alfaVbeta3 , Peptídeos , Integrina alfaVbeta3/metabolismo , Espectroscopia de Ressonância Magnética , Oligopeptídeos/química , Peptídeos/química , Preparações FarmacêuticasRESUMO
Os autores estudaram, do ponto de vista terapêutico, 30 crianças com idades variando entre dois meses e oito anos, com infecçäo do trato urinário recidivante, 60% delas com anormalidades radiológicas. O medicamento empregado foi a associaçäo rifampicina-trimetoprim, administrado por via oral na dose de 15 mg/kg/dia de rifampicina durante 10 dias. Foi constatada boa resposta clínica e laboratorial em 73,3% dos casos em controle realizado dois dias após o término do tratamento, mantendo-se negativas as culturas em 63,3% dos casos após 30 dias. Chamou atençäo a ausência de novas infecçöes nos pacientes com alteraçöes estruturais no controle tardio
