Asunto(s)
Síndrome de Boca Ardiente/diagnóstico , Candidiasis Bucal/diagnóstico , Síndrome de Sjögren/diagnóstico , Queilitis/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Enfermedades de los Labios/diagnóstico , Persona de Mediana Edad , Enfermedades de la Lengua/diagnóstico , Xerostomía/diagnósticoRESUMEN
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.
Asunto(s)
Aminoácidos/síntesis química , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Oligopéptidos/química , Aminoácidos/química , Aminoácidos/farmacología , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Línea Celular , Endopeptidasas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Imitación Molecular , Relación Estructura-ActividadRESUMEN
Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.