Synthesis and structure-activity relationship studies of cruzain and rhodesain inhibitors

Rocha, Débora Assumpção; Silva, Elany Barbosa da; Fortes, Isadora S.; Lopes, Marcela Silva; Ferreira, Rafaela Salgado; Andrade, Saulo Fernandes de

doi:10.1016/j.ejmech.2018.08.079

“…In the last years, several classes of inhibitors have shown good inhibition activity against rhodesain, [5][6][7][8][9][10][11][12] including the Michael acceptors, the most studied group of inhibitors of this family of enzymes which have demonstrated efficacy in preclinical trials. [13] Based on the features of irreversible dipeptidyl vinylsulfones inhibitors, [14] González and co-workers proposed dipeptidyl enoates as alternative inhibitors of CPs.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Dual Mode of Action of Dipeptidyl Enoates in the Inhibition of Rhodesain Cysteine Proteases

Arafet

¹

,

González

²

,

Moliner

³

2021

Chemistry A European J

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A computational study of the two possible inhibition mechanisms of rhodesain cysteine protease by the dipeptidyl enoate Cbz‐Phe‐Leu‐CH=CH−CO2C2H5 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The low free energy barriers confirm that the Cys25 residue can attack both Cβ and C1 atoms of the inhibitor, confirming a dual mode of action in the inhibition of the rhodesain by enoates. According to the results, the inhibition process through the Cys25 attack on the Cβ atom of the inhibitor is an exergonic and irreversible process, while the inhibition process when Cys25 attacks on the C1 atom of the inhibitor is and exergonic but reversible process. The interactions between the inhibitor and rhodesain suggest that P2 is the most important fragment to consider in the design of new efficient inhibitors of rhodesain. These results may be useful for the design of new inhibitors of rhodesain and other related cysteine proteases based on dipeptidyl enoates scaffolds.

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“…That is the only difference in the S2 pocket of these parasitic enzymes, resulting in a more open pocket. While several classes of inhibitors binding both to cruzain and TbrCatL have been described 12 , studies with a series of benzimidazole inhibitors provide an example of different structure-activity relationships for the two enzymes [39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

“…The term 'cruzipain' refers to the native enzyme 10,11 , whereas its recombinant form lacking the C-terminal extension was named 'cruzain' 2 . Several classes of cruzain inhibitors have been described, these include vinyl sulfones, tetra uorophenoxymethyl ketones, benzimidazoles, oxyguanidine derivatives, and peptidyl nitroalkenes 12 . These compounds have shown e cacy against T. cruzi in vitro as well as in animal models of infection 13,14 .…”

Section: Introductionmentioning

confidence: 99%

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

Santos

¹

,

Oliveira

²

,

Campos

³

et al. 2021

Preprint

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Cruzipains are the main papain-like cysteine proteases of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. Encoded by a multigenic family, previous studies have estimated the presence of dozens of copies spread over multiple chromosomes in different parasite strains. Here, we describe the complete gene repertoire of cruzipain in three parasite strains, their genomic organization, and expression pattern throughout the parasite life cycle. Furthermore, we have analyzed primary sequence variations among distinct family members as well as structural differences between the main groups of cruzipains. Based on phylogenetic inferences and residue positions crucial for enzyme function and specificity, we propose the classification of cruzipains into two families (I and II), whose genes are distributed in two or three separate clusters in the parasite genome, according with the strain. Family I comprises nearly identical copies to the previously characterized cruzipain 1/cruzain, whereas Family II encompasses three structurally distinct sub-types, named cruzipain 2, cruzipain 3, and cruzipain 4. RNA-seq data derived from the CL Brener strain indicates that Family I genes are mainly expressed by epimastigotes, whereas trypomastigotes mainly express Family II genes. Significant differences in the active sites among the enzyme sub-types were also identified, which may play a role in their substrate selectivity and impact their inhibition by small molecules.

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“…The term ‘cruzipain’ refers to the native enzyme 10 , 11 , whereas its recombinant form lacking the C-terminal extension was named ‘cruzain’ 2 . Several classes of cruzain inhibitors have been described, these include vinyl sulfones, tetrafluorophenoxymethyl ketones, benzimidazoles, oxyguanidine derivatives, and peptidyl nitroalkenes 12 . These compounds have shown efficacy against T. cruzi in vitro as well as in animal models of infection 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

Santos

¹

,

Oliveira

²

,

Campos

³

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Cruzipains are the main papain-like cysteine proteases of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. Encoded by a multigenic family, previous studies have estimated the presence of dozens of copies spread over multiple chromosomes in different parasite strains. Here, we describe the complete gene repertoire of cruzipain in three parasite strains, their genomic organization, and expression pattern throughout the parasite life cycle. Furthermore, we have analyzed primary sequence variations among distinct family members as well as structural differences between the main groups of cruzipains. Based on phylogenetic inferences and residue positions crucial for enzyme function and specificity, we propose the classification of cruzipains into two families (I and II), whose genes are distributed in two or three separate clusters in the parasite genome, according with the strain. Family I comprises nearly identical copies to the previously characterized cruzipain 1/cruzain, whereas Family II encompasses three structurally distinct sub-types, named cruzipain 2, cruzipain 3, and cruzipain 4. RNA-seq data derived from the CL Brener strain indicates that Family I genes are mainly expressed by epimastigotes, whereas trypomastigotes mainly express Family II genes. Significant differences in the active sites among the enzyme sub-types were also identified, which may play a role in their substrate selectivity and impact their inhibition by small molecules.

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Synthesis and structure-activity relationship studies of cruzain and rhodesain inhibitors

Cited by 35 publications

References 82 publications

Elucidating the Dual Mode of Action of Dipeptidyl Enoates in the Inhibition of Rhodesain Cysteine Proteases

Elucidating the Dual Mode of Action of Dipeptidyl Enoates in the Inhibition of Rhodesain Cysteine Proteases

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites

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