Comparison of Efficacies of Cysteine Protease Inhibitors against Five Strains of
            <i>Plasmodium falciparum</i>

Singh, Ajay Kumar; Rosenthal, Philip J.

doi:10.1128/aac.45.3.949-951.2001

Cited by 88 publications

(71 citation statements)

References 15 publications

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“…Over the past years the development of small molecule inhibitors against Pf falcipains has received a lot of attention by both the pharmaceutical industry and the medicinal chemistry community. Indeed, most studies in this area have shown that falcipain inhibitors prevent hemoglobin hydrolysis, block parasite development and cure murine malaria [11][12][13]. Moreover, the combination of high-throughput screening, molecular modeling methods and the availability of X-ray structures of falcipains has contributed to the discovery of potent inhibitors able to inactivate these Pf enzymes in a reversible or irreversible manner [7,14].…”

Section: Introductionmentioning

confidence: 99%

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

Teixeira

Gomes

Couesnon

et al. 2011

J Comput Aided Mol Des

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Comparative molecular field analysis (CoM-FA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoM-SIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

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Section: Introductionmentioning

confidence: 99%

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

Teixeira

Gomes

Couesnon

et al. 2011

J Comput Aided Mol Des

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“…Structureguided approaches have already proven indispensable in the design of potent and highly selective inhibitors against the closest known structural homolog of falcipain-2, cruzipain (cruzain), from T. cruzi (the causative agent of Chagas disease) (46,47,61,62). An experimental cure for Chagas disease in mice using optimized vinyl-sulfone-derivatized pseudopeptides has been reported (63), and similar vinyl-sulfone inhibitors have shown marked antimalarial effects in mice (with up to a 40% cure rate after 4 days of oral administration) (64) and broad activity across multiple P. falciparum strains (65).…”

Section: Structural Determinants Of Protein Folding and Hemoglobinmentioning

confidence: 99%

Structural and Functional Characterization of Falcipain-2, a Hemoglobinase from the Malarial Parasite Plasmodium falciparum

Hogg

Nagarajan

Herzberg

et al. 2006

Journal of Biological Chemistry

109

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Malaria is caused by protozoan erythrocytic parasites of the Plasmodium genus, with Plasmodium falciparum being the most dangerous and widespread disease-causing species. Falcipain-2 (FP-2) of P. falciparum is a papain-family (C1A) cysteine protease that plays an important role in the parasite life cycle by degrading erythrocyte proteins, most notably hemoglobin. Inhibition of FP-2 and its paralogues prevents parasite maturation, suggesting these proteins may be valuable targets for the design of novel antimalarial drugs, but lack of structural knowledge has impeded progress toward the rational discovery of potent, selective, and efficacious inhibitors. As a first step toward this goal, we present here the crystal structure of mature FP-2 at 3.1 Å resolution, revealing novel structural features of the FP-2 subfamily proteases including a dynamic ␤-hairpin hemoglobin binding motif, a flexible N-terminal ␣-helical extension, and a unique active-site cleft. We also demonstrate by biochemical methods that mature FP-2 can proteolytically process its own precursor in trans at neutral to weakly alkaline pH, that the binding of hemoglobin to FP-2 is strictly pH-dependent, and that FP-2 preferentially binds methemoglobin over hemoglobin. Because the specificity and proteolytic activity of FP-2 toward its multiple targets appears to be pH-dependent, we suggest that environmental pH may play an important role in orchestrating FP-2 function over the different life stages of the parasite. Moreover, it appears that selectivity of FP-2 for methemoglobin may represent an evolutionary adaptation to oxidative stress conditions within the host cell.

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“…Drug resistance might also develop by other mechanisms, including increases in target enzyme expression and diminished intracellular accumulation of an inhibitor. Earlier, we evaluated five strains of P. falciparum, which vary greatly in their sensitivities to established antimalarial drugs, and showed no differences in their sensitivities to cysteine protease inhibitors (17). However, the likelihood of selection of resistance of P. falciparum to protease inhibitors has not previously been explored.…”

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confidence: 99%

Selection of Cysteine Protease Inhibitor-resistant Malaria Parasites Is Accompanied by Amplification of Falcipain Genes and Alteration in Inhibitor Transport

Singh

Rosenthal

2004

Journal of Biological Chemistry

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Cysteine protease inhibitors are being studied as possible new antimalarial agents. To evaluate the potential for resistance to these compounds, we subjected chloroquine-resistant (W2 strain) Plasmodium falciparum to increasing concentrations of a vinyl sulfone cysteine protease inhibitor. After incubation with 1-200 nM morpholine urea-leucine-homophenylalanine-phenyl vinyl sulfone over approximately 8 months, highly resistant parasites (ϳ100-fold increases in IC 50 ) were selected. The vinyl sulfone-resistant parasites were also resistant to related peptidyl inhibitors, but had only modest (ϳ2-fold) decreases in sensitivity to other cysteine protease inhibitors. Compared with the parental strain, resistant parasites showed no changes in multiplication rates, but elevations in cysteine protease activity, falcipain-2 and falcipain-3 copy numbers, transcription of falcipain genes, and levels of these target proteases in trophozoites. Resistant parasites grown in the absence of the vinyl sulfone for 12 weeks showed partial reversion, with increased inhibitor sensitivity and apparent decreases in copy numbers of falcipain-2 and falcipain-3. The sequences of falcipain-1, falcipain-2, and falcipain-3 were identical in sensitive and resistant parasites. The accumulation of a vinyl sulfone inhibitor was decreased approximately 9-fold in resistant parasites. In summary, parasites resistant to a cysteine protease inhibitor were selected, although the acquisition of high level resistance required extended exposure to the inhibitor and this resistance was somewhat unstable. Resistance was specific for the type of protease inhibitor used for the selection and appeared to be mediated both by alterations in inhibitor transport and by a previously unidentified mechanism in P. falciparum, the amplification of genes encoding targets of enzyme inhibitors.

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Comparison of Efficacies of Cysteine Protease Inhibitors against Five Strains of Plasmodium falciparum

Cited by 88 publications

References 15 publications

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

Structural and Functional Characterization of Falcipain-2, a Hemoglobinase from the Malarial Parasite Plasmodium falciparum

Selection of Cysteine Protease Inhibitor-resistant Malaria Parasites Is Accompanied by Amplification of Falcipain Genes and Alteration in Inhibitor Transport

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