Peptidase Inhibitors as a Possible Therapeutic Strategy for Chagas Disease

Novel Therapeutic Strategies for Chagas` Disease

“…Peptidases, such as, serine, threonine, aspartyl, metallo and cysteine peptidases have been detected in Trypanosoma cruzi and they have been shown to be involved in numerous roles in the physiology of the parasite. The inhibition of some of these enzymes has shown high anti-T. cruzi activity in vitro and in vivo (Capaci-Rodrigues, 2010). The serine peptidases described in Trypanosoma cruzi include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca 2+ signaling during mammalian cell invasion; a 80-kDa prolyl serine oligopeptidase (POP Tc80), belonging to the prolyl oligopeptidase family (EC 3.4.21.26) against which inhibitors are being developed, and a lysosomal serine carboxypeptidase that probably hydrolyzes human collagen (Types I and IV) and fibronectin that has been implicated in the parasite adhesion to host cells and cell entry (Burleigh, 1995;Burleigh, 1997;Caler, 1998;Grellier, 2001;Bastos, 2005;da Silva-Lopez, 2008).…”

“…Cruzipain is involved in a number of cellular processes and in important virulence factors in the pathogenesis of parasitic diseases, such as: in the cell invasion phenomenon, facilitating the proteolytic degradation of host tissues and triggering the evasion mechanism (Franke de Cazzulo, 1994;Costales, 2007;Capaci-Rodrigues, 2010;. In addition, this CP has demonstrated an ability to induce the production of the proinflammatory peptide Lys-bradykinin by the proteolysis of kininogen or by activation of plasmatic pre-kallikrein (Del Nery, 1997;Benítez-Hernández, 2010;Capaci-Rodrigues, 2010 (Garcia, 1998;Yong, 2000;Duschak, 2006;Capaci-Rodrigues, 2010).…”

“…In addition, this CP has demonstrated an ability to induce the production of the proinflammatory peptide Lys-bradykinin by the proteolysis of kininogen or by activation of plasmatic pre-kallikrein (Del Nery, 1997;Benítez-Hernández, 2010;Capaci-Rodrigues, 2010 (Garcia, 1998;Yong, 2000;Duschak, 2006;Capaci-Rodrigues, 2010). The structure of the active site, of the cruzipain , has been reported through X-ray crystal structures of the enzyme in complex with reversible and irreversible inhibitors.…”

“…14. Mechanism of irreversible inhibition of cysteine peptidase by vinyl sulfones (Palmer, 1995;Powers, 2002;Capaci-Rodrigues, 2010) The most important peptidyl vinyl sulfone derivative is K11777 (N-methyl-piperazine-PhehomoPhe-vinylsulfone-phenyl), also known as K777 (compound 6, Figure 15) that is currently in late-stage preclinical trials. K11777 is a second generation vinyl sulfone (Roush, 2001 , 2010).…”

Búsqueda racional de nuevos fármacos antichagásicos inhibidores de la cruzipaína

“…En cuanto a la relevancia funcional de Cz, la misma juega un rol importante en diversas funciones del parásito tales como la invasión de las células huésped, degradando tejidos del huésped y facilitando la penetración del parásito en las células (Aparicio et al, 2004) y participando en la evasión de la respuesta inmune por diferentes mecanismos (Benitez-Hernandez et al, 2010). La participación de la enzima en la proliferación de epimastigotes y amastigotes y en la metaciclogénesis también ha sido demostrada (Santos et al, 2005;Tomas and Kelly, 1996); por otro lado, dada su función autocatalítica, la inhibición de Cz conduce a la acumulación de un precursor en el aparato de Golgi, provocando importantes alteraciones morfológicas, dando lugar eventualmente a un shock osmótico y a la muerte de T. cruzi; estos cambios morfológicos en el aparato de Golgi se han observado en parásitos tratados con diferentes inhibidores, lo cual sugiere que independientemente del mecanismo de inhibición, todos los inhibidores de Cz producen el mismo efecto (Capaci Rodrigues et al, 2010;McKerrow et al, 2009).…”