RESUMO
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.
Assuntos
Catepsinas/síntese química , Dipeptídeos/síntese química , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Linfócitos B/efeitos dos fármacos , Ligação Competitiva , Catepsinas/química , Catepsinas/farmacologia , Linhagem Celular , Cristalografia por Raios X , Dipeptídeos/química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.