RESUMEN
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
Asunto(s)
Catepsinas/síntesis química , Dipéptidos/síntesis química , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Linfocitos B/efectos de los fármacos , Unión Competitiva , Catepsinas/química , Catepsinas/farmacología , Línea Celular , Cristalografía por Rayos X , Dipéptidos/química , Dipéptidos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.