Contribution to New Therapies for Chagas Disease

Doyle, Patricia S.; Engel, Juan C.

doi:10.1002/9783527670383.ch25

Cited by 1 publication

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“…A cruzaína (GP57/51, EC 3.4.22.51, também chamada de cruzipaína na sua forma nativa) é a cisteíno protease majoritária no T. cruzi, expressa em todos os estágios do seu ciclo de vida, como diversas isoformas similares (2,16,23). Pode ser encontrada em vesículas intracelulares no estágio dormente do parasito, em ambiente químico ácido (pH ≈ 5,5), mas, na forma amastigota, está também presente na superfície do parasito, em contato com o citoplasma do hospedeiro e, consequentemente, em ambiente neutro (pH ≈ 7,4) (19,21,24).…”

Section: Cruzaína a Principal Cisteíno Protease Do Trypanosoma Cruziunclassified

“…A cruzaína é essencial para o desenvolvimento do parasito dentro do hospedeiro, por estar associada a funções como penetração dos tripomastigotas nas células humanas, remodelamento molecular dos epimastigotas para tripomastigotas, nutrição e evasão do sistema imune. Além disso, também está relacionada à ativação da resposta inflamatória (9,16,19,21,22,25).…”

Section: Cruzaína a Principal Cisteíno Protease Do Trypanosoma Cruziunclassified

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Atividade anti->i<Trypanosoma cruzi>/i< de agentes não-peptídicos como inibidores da cisteíno protease cruzaína

Lameiro¹

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Chagas disease, caused by the protozoan Trypanosoma cruzi, was first described in 1909 by the Brazilian physician Carlos Chagas. Despite being known for over a hundred years, treatments for this disease are currently limited to only two drugs that, besides generating side effects, are not capable of eliminating the parasites from the host body in the chronic phase of the disease. In the context of developing new drugs for Chagas disease, the cysteine protease cruzain stands out as a molecular target for inhibition, due to its essential role in the life cycle of the trypanosome. In this work, compounds derived from Neq0594, a trypanocidal agent and cruzain inhibitor previously developed in NEQUIMED/IQSC/USP, were produced. These derivatives have their structures based on dipeptides, which are the natural substrate of cruzain, but, because they have a 2,2,2-trifluoroethylamine group replacing a peptide bond, and fluorine atoms substituting hydrogen atoms, they must be more bioavailable and metabolically stable than their peptide analogues. Fifteen derivatives of Neq0594 were synthesized, purified and characterized (1 H-NMR, 13 C-NMR, FTIR, HRMS, polarimetry and melting point) for the structure-activity relationship study. The compounds were tested for cruzain, LmCPB and cathepsin L and displayed activities equal to or better than the lead compound for cruzain. It was also observed the preference of this enzyme for compounds with the isobutyl group at P2 and (S,S) configuration, as well as the bioisosterism of the H/F replacement. The results also suggest the presence of crossed structure-activity relationships between the protozoan cysteine proteases (cruzain and LmCPB). Moreover, computer simulations using the molecular dynamics method were performed to explore the interactions of three compounds with cruzain. The simulations demonstrated the major hydrogen bonds with the residues Gly66 and Asp161, hydrophobic interactions at P2 and P3 and the absence of polar interactions with the P3 fluorine atoms. Lista de Esquemas Esquema 1-Formação do par iônico e mecanismo geral de hidrólise por cisteíno proteases.

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Section: Cruzaína a Principal Cisteíno Protease Do Trypanosoma Cruziunclassified

Atividade anti->i<Trypanosoma cruzi>/i< de agentes não-peptídicos como inibidores da cisteíno protease cruzaína

Lameiro¹

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Contribution to New Therapies for Chagas Disease

Cited by 1 publication

References 61 publications

Atividade anti->i<Trypanosoma cruzi>/i< de agentes não-peptídicos como inibidores da cisteíno protease cruzaína

Atividade anti->i<Trypanosoma cruzi>/i< de agentes não-peptídicos como inibidores da cisteíno protease cruzaína

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