RESUMEN
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.
Asunto(s)
Isomerasas de Aminoácido/antagonistas & inhibidores , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Clostridioides difficile/efectos de los fármacos , Enterocolitis Seudomembranosa/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/farmacología , Compuestos de Fenilurea/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Isomerasas de Aminoácido/genética , Isomerasas de Aminoácido/metabolismo , Animales , Antibacterianos/síntesis química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Clostridioides difficile/enzimología , Clostridioides difficile/genética , Clostridioides difficile/crecimiento & desarrollo , Diseño de Fármacos , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/mortalidad , Enterocolitis Seudomembranosa/patología , Femenino , Expresión Génica , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/crecimiento & desarrollo , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Compuestos de Fenilurea/síntesis química , Pirroles/síntesis química , Quinolinas/síntesis química , Especificidad de la Especie , Relación Estructura-Actividad , Análisis de SupervivenciaRESUMEN
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Concentración de Iones de Hidrógeno , Unión Proteica , Relación Estructura-ActividadRESUMEN
A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.
Asunto(s)
Amidas/química , Endopeptidasas/metabolismo , Inhibidores de Proteasas/síntesis química , Secretasas de la Proteína Precursora del Amiloide , Sitios de Unión , Inmunoensayo , Péptidos/química , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
