RESUMEN
The screening of a library of small molecule peptidomimetics toward secreted aspartic proteinase-2 (SAP2) of Candida albicans allowed us to identify two compounds that showed in vitro inhibitory potency comparable to pepstatin A. In an experimental model of vaginal candidiasis, the two candidate compounds were as active as a therapeutic dose of fluconazole. Importantly, this activity was fully preserved when the challenger was a fluconazole-resistant strain of the fungus. Altogether, our data demonstrate SAP2 as a valid C. albicans target for the development of new drugs against this important human pathogen.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Candida albicans/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Animales , Antifúngicos/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Candida albicans/enzimología , Candida albicans/patogenicidad , Candidiasis/microbiología , Candidiasis/prevención & control , Relación Dosis-Respuesta a Droga , Farmacorresistencia Fúngica/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Fluconazol/farmacología , Proteínas Fúngicas/metabolismo , Humanos , Modelos Químicos , Estructura Molecular , Pepstatinas/química , Biblioteca de Péptidos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , VirulenciaRESUMEN
Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).