RESUMEN
The development of a sensitive, yet reliable assay for the analysis of botulinum neurotoxin A (BoNT/A) inhibitors is described; using this assay a new protease inhibitor was characterized and found to be one of the most potent inhibitors reported to date.
Asunto(s)
Adamantano/química , Adamantano/farmacología , Toxinas Botulínicas Tipo A/antagonistas & inhibidores , Toxinas Botulínicas Tipo A/química , Evaluación Preclínica de Medicamentos/métodos , Adamantano/análogos & derivados , Unión Competitiva , Catálisis , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Fluorescencia , Espectrometría de Masas , Sensibilidad y EspecificidadRESUMEN
Protein-protein interactions are of critical importance in biological systems, and small molecule modulators of such protein recognition and intervention processes are of particular interest. To investigate this area of research, we have synthesized small-molecule libraries that can disrupt a number of biologically relevant protein-protein interactions. These library members are designed upon planar motif, appended with a variety of chemical functions, which we have termed "credit-card" structures. From two of our "credit-card" libraries, a series of molecules were uncovered which act as inhibitors against the HIV-1 gp41 fusogenic 6-helix bundle core formation, viral antigen p24 formation, and cell-cell fusion at low micromolar concentrations. From the high-throughput screening assays we utilized, a selective index (SI) value of 4.2 was uncovered for compound 2261, which bodes well for future structure activity investigations and the design of more potent gp41 inhibitors.