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

Jaudzems, Kristaps; Tars, K.; Maurops, G.; Ivdra, N.; Otikovs, Mārtiņš; Leitans, Janis; Kanepe, I.; Domračeva, Ilona; Mutule, Ilze; Trapencieris, Pēteris; Blackman, Michael J.; Jirgensons, Aigars

doi:10.1021/ml4004952

Cited by 50 publications

(56 citation statements)

References 21 publications

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“…Docking of 49c showed comparable binding mode on the three modeled structures (RMSD 1.57 Å ;Fig 2B and D). As described for other hydroxy-ethylamine compounds, the catalytic dyad (D299-D490 in TgASP3) interacts with the central hydroxyl group, which mimics the transition-state formed during the cleavage of the peptide (Jaudzems et al, 2014). A second hydrogen bond that strengthens the binding interaction is formed between the benzamide and the backbone carbonyl group of the glycine G492 in TgASP3 (G497 in PfPMIX and G453 in PfPMX).…”

Section: Docking Of Hydroxy-ethylamine Scaffold-based Compounds On Thmentioning

confidence: 94%

Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

et al. 2018

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aspartyl protease 3 (TgASP3) phylogenetically clusters with Plasmepsins IX and X (PfPMIX, PfPMX). These proteases are essential for parasite survival, acting as key maturases for secreted proteins implicated in invasion and egress. A potent antimalarial peptidomimetic inhibitor (49c) originally developed against Plasmepsin II selectively targets TgASP3, PfPMIX, and PfPMX To unravel the molecular basis for the selectivity of 49c, we constructed homology models of PfPMIX, PfPMX, and TgASP3 that were first validated by identifying the determinants of microneme and rhoptry substrate recognition. The flap and flap-like structures of several reported Plasmepsins are highly flexible and critically modulate the access to the binding cavity. Molecular docking of 49c to TgASP3, PfPMIX, and PfPMX models predicted that the conserved phenylalanine residues in the flap, F344, F291, and F305, respectively, account for the sensitivity toward 49c. Concordantly, phenylalanine mutations in the flap of the three proteases increase twofold to 15-fold the IC values of 49c. Compellingly the selection of mutagenized resistant strains to 49c reproducibly converted F344 to a cysteine residue.

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Section: Docking Of Hydroxy-ethylamine Scaffold-based Compounds On Thmentioning

confidence: 94%

Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

et al. 2018

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“…Digestive plasmepsins (Plm I, II, IV and HAP) are involved in the processing of hemoglobin to amino acids, however, their inhibition may not be sufficient to kill the parasite due to alternative pathways of hemoglobin digestion . Recent investigations suggest that the anti‐malarial activity in red blood cell (RBC) assays likely can be achieved by targeting the non‐digestive Plms such as Plm V, Plm IX, and Plm X, which are expressed in the blood stage. Of these, Plm V triggers the export protein transfer from parasitic vacuole to the RBC, Plm IX is involved in merozoite invasion of RBC while Plm X is involved in both, the invasion and the egress of merozoites.…”

Section: Introductionmentioning

confidence: 99%

Azole‐based non‐peptidomimetic plasmepsin inhibitors

Kinena

Leitis

Kanepe

et al. 2018

Archiv der Pharmazie

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The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases - plasmepsins (Plms) - are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.

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“…The sequence similarity among the different species is between 70 and 87% (Bernstein et al, 2003). Therefore, there is a growing interest in the structural characterization of this class of enzymes to aid structure-based drug design (Jaudzems et al, 2014;Recacha et al, 2015;Rasina et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure ofPlasmodium falciparumproplasmepsin IV: the plasticity of proplasmepsins

Recacha¹,

Jaudzems²,

Akopjana³

et al. 2016

Acta Cryst Sect F

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Plasmepsin IV from Plasmodium falciparum (PM IV) is a promising target for the development of novel antimalarial drugs. Here, the crystal structure of the truncated zymogen of PM IV (pPM IV), consisting of the mature enzyme plus a prosegment of 47 residues, has been determined at 1.5 Å resolution. pPM IV presents the fold previously described for studied proplasmepsins, displaying closer similarities to proplasmepin IV from P. vivax (pPvPM) than to the other two proplasmepsins from P. falciparum. The study and comparison of the pPM IV structure with the proplasmepsin structures described previously provide information about the similarities and differences in the inactivation-activation mechanisms among the plasmepsin zymogens.

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

Cited by 50 publications

References 21 publications

Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

Azole‐based non‐peptidomimetic plasmepsin inhibitors

Crystal structure ofPlasmodium falciparumproplasmepsin IV: the plasticity of proplasmepsins

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