Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library

Carroll, Carolyn DiIanni; Patel, Hitesh D.; Johnson, Theodore; Guo, Tao; Orlowski, Marc; Zhenmin, He; Cavallaro, Cullen L.; Guo, Joan; Oksman, Anna; Gluzman, Ilya Y.; Connelly, James; Chelsky, Daniel; Goldberg, Daniel E.; Dolle, Roland E.

doi:10.1016/s0960-894x(98)00419-3

Cited by 69 publications

(60 citation statements)

References 11 publications

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“…Inhibitors of PLM II that have low nanomolar inhibition constant values and are lethal against cultured malarial parasites have been identi®ed Carroll, Patel et al, 1998;Goldberg, 1992;Goldberg et al, 1991;Haque et al, 1999;Silva et al, 1996Silva et al, , 1998Westling et al, 1999). Furthermore, some aspartic and cysteine protease inhibitors demonstrate an apparent synergistic inhibition of hemoglobin degradation in both culture and a murine malaria model (Semenov et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Asojo

Afonina

Gulnik

et al. 2002

Acta Crystallogr D Biol Cryst

117

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Plasmepsin II is one of the four catalytically active plasmepsins found in the food vacuole of Plasmodium falciparum. These enzymes initiate hemoglobin degradation by cleavage at the -chain between Phe33 and Leu34. The crystal structures of Ser205 mutant plasmepsin II from P. falciparum in complex with two inhibitors have been re®ned at a resolution of 1.8 A Ê in the space group I222 and to R factors of 19.9 and 19.5%. Each crystal contains one monomer in the asymmetric unit. Both inhibitors have a Phe± Leu core and incorporate tetrahedral transition-state mimetic hydroxypropylamine. The inhibitor rs367 possesses a 2,6-dimethylphenyloxyacetyl group at the P2 position and 3-aminobenzamide at the P2 H position, while rs370 has the same P2 group but 4-aminobenzamide in the P2 H position. These complexes reveal key conserved hydrogen bonds between the inhibitor and the binding-cavity residues, notably with the¯ap residues Val78 and Ser79, the catalytic dyad Asp34 and Asp214 and the residues Ser218 and Gly36 that are in proximity to the catalytic dyad. The structures also show unexpected conformational variability of the binding cavity of plasmepsin II and may re¯ect the mode of binding of the hemoglobin -chain for cleavage.

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Section: Introductionmentioning

confidence: 99%

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Asojo

Afonina

Gulnik

et al. 2002

Acta Crystallogr D Biol Cryst

117

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“…The ratio of the IC 50 values was chosen as an indicator of cell penetration of the synthesized inhibitors; the number will increase along with the impairment to cross cell membranes. A linear correlation (r ) 0.86) between lipophilicity and activity ratio was obtained for all compounds but one (9).…”

Section: Resultsmentioning

confidence: 78%

“…[9][10][11] Considering the redundancy of PLMs, 12,13 it is therefore necessary to design compounds able to inhibit two or more in this enzyme family in order to develop drugs active on P. falciparum. Some of the synthesized compounds, designed as PLM II inhibitors, are also strong inhibitors of PLM I, which is, in view of the recent literature, a prerequisite for developing new antimalarial agents.…”

Section: Discussionmentioning

confidence: 99%

High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors

et al. 2006

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The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the “double-drug” approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC50) as low as 0.1 μM was obtained, an excellent improvement in comparison with inhibitors previously reported (IC50 = 2−20 μM). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K i = 1−700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 μM and were highly selective for PLMs vs human cathepsin D.

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“…Protease inhibitors specific for plasmepsins I and II and falcipain are being explored for the development of novel lead compounds for use in patients with malaria (5,6,23,24). In view of the low mammalian toxicity of bestatin (26) and the synergies demonstrated here, it appears that aminopeptidase inhibitors, whether used alone or simultaneously with aspartyl and cysteine protease inhibitors, may also have considerable potential.…”

Section: Resultsmentioning

confidence: 98%

Analysis of Antimalarial Synergy between Bestatin and Endoprotease Inhibitors Using Statistical Response-Surface Modelling

Gavigan¹,

Machado

Dalton

et al. 2001

Antimicrob Agents Chemother

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The pathway of hemoglobin degradation by erythrocytic stages of the human malarial parasite Plasmodium falciparum involves initial cleavages of globin chains, catalyzed by several endoproteases, followed by liberation of amino acids from the resulting peptides, probably by aminopeptidases. This pathway is considered a promising chemotherapeutic target, especially in view of the antimalarial synergy observed between inhibitors of aspartyl and cysteine endoproteases. We have applied response-surface modelling to assess antimalarial interactions between endoprotease and aminopeptidase inhibitors using cultured P. falciparum parasites. The synergies observed were consistent with a combined role of endoproteases and aminopeptidases in hemoglobin catabolism in this organism. As synergies between antimicrobial agents are often inferred without proper statistical analysis, the model used may be widely applied in studies of antimicrobial drug interactions.Malaria remains one of the world's most important infectious diseases, and new antimalarial drugs are urgently needed, especially in areas where drug-resistant strains of the most lethal human malarial parasite, Plasmodium falciparum, are prevalent (21,22,30). The pathway of hemoglobin degradation by intraerythrocytic stages of P. falciparum has received a lot of attention as a potential therapeutic target (5). The parasite ingests large quantities of erythrocyte cytosol, polymerizing the heme moiety of hemoglobin into harmless crystalline inclusions (hemozoin) and digesting the globin to provide many of the amino acids required for protein synthesis. To date, most models have proposed that aspartyl proteases (plasmepsins I and II), cysteine protease (falcipain), and metalloproteases (falcilysin) are involved in hemoglobin degradation within a unique organelle, the digestive (food) vacuole (8,10,13,14,17,25,29). The growth-inhibitory actions of certain combinations of endoprotease inhibitors, especially those specific for aspartyl and cysteine protease classes, are synergistic on cultured parasites and possibly in animal models of malaria (1,25,27). The mechanism of synergy is unclear but may be related to the idea that endoproteases act sequentially in the same catabolic pathway. Accordingly, the possibility of developing combination therapy to target concomitantly more than one protease of the hemoglobinolytic pathway has become attractive.The aminopeptidase-specific inhibitors bestatin and nitrobestatin block malarial parasite growth in culture (20), and it is thought that one or more Plasmodium aminopeptidases are required for the terminal stages of hemoglobin breakdown, exoproteolytically cleaving globin-derived peptides to liberate free amino acids for incorporation into parasite proteins (7,12,17). Therefore, the aim of the present study was to investigate whether aminopeptidase and endoprotease inhibitors would act synergistically on the growth of cultured P. falciparum.A serious deficiency of the analysis of many published antimicrobial synergy and antagonism d...

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Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library

Cited by 69 publications

References 11 publications

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

Structures of Ser205 mutant plasmepsin II fromPlasmodium falciparumat 1.8 Å in complex with the inhibitors rs367 and rs370

High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors

Analysis of Antimalarial Synergy between Bestatin and Endoprotease Inhibitors Using Statistical Response-Surface Modelling

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