Plasmepsins as Potential Targets for New Antimalarial Therapy

Ersmark, Karolina; Samuelsson, Bertil; Hallberg, Anders

doi:10.1002/chin.200647253

Cited by 32 publications

(57 citation statements)

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“…Modifications of R 1 , R 2 , and R 4 were also expected to contribute to the selectivity versus CatD as these moieties are located in the S1′ and S2 and S4 pockets that are most different between the two enzymes. 21 Keeping R 4 substituent (2-(1,2-thiazinane-1,1-dioxide)) constant while optimizing substituents R 1 −R 3 proved to be impractical due to the very lengthy synthesis. Therefore, we preferred to use the more accessible piperidinyl group as the R 4 substituent for optimization around R 1 −R 3 .…”

Section: Espite Extensive Eradication Campaigns Malaria Caused Bymentioning

confidence: 99%

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Jaudzems

Tars

Maurops

et al. 2014

ACS Med. Chem. Lett.

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Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

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Section: Espite Extensive Eradication Campaigns Malaria Caused Bymentioning

confidence: 99%

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Jaudzems

Tars

Maurops

et al. 2014

ACS Med. Chem. Lett.

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“…Four pepsin-like aspartic proteases, named plasmepsins (PM I-IV), are involved in haemoglobin breakdown in Plasmodium falciparum, which causes the most fatal form of malaria. As PMs are unique to Plasmodia, these enzymes are regarded as potential drug targets [1]. However, despite their pharmaceutical significance, the dynamics of PMs have only recently started to be investigated by computational studies [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

The protonation state of the catalytic aspartates in plasmepsin II

Friedman

Caflisch

2007

FEBS Letters

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Assigning the correct protonation state to the catalytic residues is essential for a realistic modelling of an enzyme's active site. Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by Plasmodium spp. In aspartic proteases, one of the two catalytic aspartates is protonated, while the other is negatively charged. Here, multiple explicit-water molecular dynamics simulations of plasmepsin II, uncomplexed and with a hydroxypropylamine peptidomimetic inhibitor, indicate that protonation of Asp214 favours a stable active site structure. Moreover, the protonation state of the catalytic aspartate has a strong influence on a linear chain of hydrogen bonds with the adjacent side chains.

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“…It has also been established that [35], plm II is capable of degrading erythrocyte skeleton components spectrin, actin, and protein 4.1 at neutral pH and used specific antibodies to localize plm II to the periphery of the parasite during the merozoite stage, implying that plm II plays a role in mature merozoite escape from the erythrocyte host by cytoskeletal degradation [36]. Plasmepsin II (plm II) is the most extensively characterized of these enzymes since several crystal structures have been determined [37,38,39] and potent inhibitors developed [40,41,42,43,44]. Silva et al [37] determined the first crystal structure of the plm family showing recombinant plm II complexed with pepstatin A, a known aspartic protease inhibitor whose inhibition constant for plm II is 0.006 nM.…”

Section: Introductionmentioning

confidence: 99%

In-silico Antimalarial Study of Monocarbonyl Curcumin Analogs and Their 2,4-Dinitro Phenylhydrazones Using the Inhibition of Plasmepsin II as Test Model

Fadare¹,

Iwalewa²,

Obafemi³

et al. 2017

AJPS

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A well-known component of the Indian spice turmeric, curcumin, has received a lot of attention in recent years as a potential antimalarial agent but the inherent problems associated with low bioavailabilty tends to limit its applicability. The bioavailability is linked to its low solubility in water and its rapid break down in the blood plasma. In this study, we have proposed the use of synthetic analogs of curcumin and their derivatives which are expected to be less prone to degradation in the blood plasma as possible antimalarials. The binding affinity of monocarbonyl analogs of curcumin and their 2,4-dinitrophenylhydrazone derivatives for the chain A domain of plasmepsin II, one of the key enzymes involved in hemoglobin digestion in the food vacuole of the malaria parasite was determined by computational docking analysis, performed using Auto Dock Vina 1.1.2, pymol and Chem 3D ultra 12.0. The binding energies of the 20 compounds studied was compared with that of pepstatin A (a known inhibitor of plasmepsin II), curcumin and chloroquine. The 3D structure of the protein was obtained from the protein data bank (PDB ID:1M43), the compounds' 3D structure was generated with the Chem 3D ultra 12.0 and visualization done with pymol. Out of the 20 compounds docked with plasmepsin II, 17 had binding energies higher than that of pep A (-32.6, kJ/mol) and 19 of the compounds had binding energies higher than that of curcumin (30.96, kJ/mol). The docked compounds, 5b, 6b and 7b had the highest binding energies (-44.73 kJ/mol, -42.64 kJ/mol and -41.80 kJ/mol respectively). It is expected that the compounds with binding energies higher than that of pep A may be considered for further antimalarial studies in-vitro and in-vivo.

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Plasmepsins as Potential Targets for New Antimalarial Therapy

Abstract: Organic chemistry Z 0200 Plasmepsins as Potential Targets for New Antimalarial Therapy -[168 refs.]. -(ERSMARK, K.; SAMUELSSON, B.; HALLBERG*, A.; Med. Res. Rev. 26 (2006) 5, 626-666; Dep. Med. Chem., Uppsala Univ., S-751 23 Uppsala, Swed.; Eng.) -Lindner 47-253

Cited by 32 publications

References 1 publication

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

The protonation state of the catalytic aspartates in plasmepsin II

In-silico Antimalarial Study of Monocarbonyl Curcumin Analogs and Their 2,4-Dinitro Phenylhydrazones Using the Inhibition of Plasmepsin II as Test Model

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