Evaluation of cysteine proteases of Plasmodium vivax as antimalarial drug targets: sequence analysis and sensitivity to cysteine protease inhibitors

Abstract

Cysteine proteases perform critical roles in the life cycles of malaria parasites. In Plasmodium falciparum, treatment of cysteine protease inhibitors inhibits hemoglobin hydrolysis and blocks the parasite development in vitro and in vivo, suggesting that plasmodial cysteine proteases may be interesting targets for new chemotherapeutics. To determine whether sequence diversity may limit chemotherapy against Plasmodium vivax, we analyzed sequence variations in the genes encoding three cysteine proteases, vivapain-1, -2 and -3, in 22 wild isolates of P. vivax. The sequences were highly conserved among wild isolates. A small number of substitutions leading to amino acid changes were found, while they did not modify essential residues for the function or structure of the enzymes. The substrate specificities and sensitivities to synthetic cysteine protease inhibitors of vivapain-2 and -3 from wild isolates were also very similar. These results support the suggestion that cysteine proteases of P. vivax are promising antimalarial chemotherapeutic targets.

Genetic variations of the dihydrofolate reductase gene of Plasmodium vivax in Mandalay Division, Myanmar

“…The polymorphic regions of the AMA-1 gene were amplified by PCR, and each amplified product was cloned and sequenced, as previously described (Na et al 2004).…”

Cysteine Proteinase Inhibitors as Therapy for Parasitic Diseases: Advances in Inhibitor Design

“…(3). Summary of structure-activity relationship of dipeptidyl compounds against parasite cysteine proteinases based on published data for second-order rate constants of enzyme inhibition [25,[29][30][31][32][33][34][35][36][37][38]. Cbz, carbobenzoxy; CO-Exp, epoxide ketone; CO-FMK, fluoromethyl ketone; MePip, N-methyl piperazine urea; Mu, morpholine urea; hPhe, homophenylalanine; VSOPh, phenyl vinyl sulfonate ester; VSPh, phenyl vinyl sulfone; VSNHBn, N-phenyl vinyl sulfonamide; _, favourable substituent; _, unfavourable substituent .…”

“…(3) [25,[29][30][31][32][33][34][35][36][37][38]. On the nonprime side, homo-phenylalanine (hPhe) is a favoured substituent at the P 1 position.…”

“…Over the last decade numerous dipeptidyl substrate analogues have been investigated as inhibitors of parasite cysteine proteinases [25,[29][30][31][32][33][34][35][36][37][38]. Compounds tested included peptide aldehydes (CHO), halomethyl ketones (CH 2 F, CH 2 Cl), diazomethyl ketones (CHN 2 ), epoxy ketones (Exp), vinyl sulfones (VSR), vinyl sulfonate esters (VSOR) and vinyl sulfonamides (VSNH).…”

Light-induced inhibition of papain by a {Mn–NO}6 nitrosyl: Identification of papain–SNO adduct by mass spectrometry

“…For example, the inactivation of cathepsins, cysteine proteases involved in the inflammation pathway, could lead to possible drug targets to treat rheumatoid arthritis [29]. Cysteine proteases such as vivapains are also involved in the parasitic hydrolysis of hemoglobin and parasite growth [30]. The development of inhibitors to these hemoglobinases could lead to drug candidates against malaria.…”