Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold

Ciana, Claire-Lise; Siegrist, Romain; Aissaoui, Hamed; Marx, Léo; Racine, Sophie; Meyer, Solange; Binkert, Christoph A.; Kanter, Ruben de; Fischli, Christoph; Wittlin, Sergio; Boss, Christoph

doi:10.1016/j.bmcl.2012.11.118

Cited by 32 publications

(41 citation statements)

References 18 publications

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“…Similar to PfPMIX-F291Y and PfPMX-F305Y, the docking of 49c on the TgASP3-F344Y mutant does not impose a dramatic change to the orientation of the binding mode, but causes a decrease in the predicted binding affinity (À5.5 kcal/mol) compared to the wild type (À7.1 kcal/mol; Fig 4B, upper panel). Moreover, F386, which forms the S 0 1 cavity together with other hydrophobic residues I297, .9 nM (Ciana et al, 2013) > 500 nM (Ciana et I394, I389, F391, contributes to the high lipophilic potential, nicely accommodating the phenyl moiety of 49c ( Fig 4A). In contrast, docking of 49c on ASP3-Ty-F386Y mutant shows a clear decrease in the predicted binding affinity (À4.2 kcal/mol).…”

Section: Mutation Of Phenylalanine To Tyrosine In the Flap Causes A Dmentioning

confidence: 99%

“…TgASP3 is phylogenetically related to PfPMIX and PfPMX, and members of this cluster act as maturases for microneme and rhoptry proteins, playing a crucial role in invasion and in egress in both parasites, respectively (Dogga et al, 2017;Nasamu et al, 2017;Pino et al, 2017). Moreover, among the hydroxy-ethylamine scaffold inhibitors directed against Plasmepsin II (PfPMII; Ciana et al, 2013), a few derivatives including compound 49c showed very potent antimalarial effects only after 72 h of treatment with an IC 50 of 0.6 nM. While inhibitors targeting the HIV aspartic protease are potent components of antiretroviral therapies, the inhibitors directed against the malaria hemoglobin-degrading enzymes became unattractive due to dispensability of these Plasmepsins for parasite survival (Silva et al, 1996;Coombs et al, 2001;Andrews et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Structural and sequence comparisons identified conserved phenylalanine residues in the flap and in the adjacent hydrophobic pocket predicted to be critical for the binding of 49c and for discriminating the activities of the series of derivatives of this compound (Ciana et al, 2013). The three models combined with molecular docking and in vitro experiments were used to address the question of substrate and inhibitor selectivity for this class of enzymes.…”

Section: Introductionmentioning

confidence: 99%

“…The key interactions of the catalytic dyad with the hydroxyl group of the compound are shown with black dotted lines (hydrogen bonds).ª 2018 The AuthorsThe EMBO Journal 37: e98047 | 2018 49c (IC 50~0 .9 nM against P. falciparum;Ciana et al, 2013) and 500 nM against T. gondii(Fig EV3A, The two aspartic acids are reported for completeness.…”

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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: Mutation Of Phenylalanine To Tyrosine In the Flap Causes A Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2018

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“…6–11 While a number of potent peptidomimetic inhibitors of Plasmodium aspartic proteases have been identified, 7, 12–14 we have focused on repurposing classes of drug-like aspartic protease inhibitors developed by the pharmaceutical industry for human aspartic proteases such as β-secretase (BACE) 15, 16 or renin. 17 …”

Section: Introductionmentioning

confidence: 99%

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

Meyers

Anderson

McNitt

et al. 2015

Bioorganic & Medicinal Chemistry

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Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.

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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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Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold

Cited by 32 publications

References 18 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

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

Azole‐based non‐peptidomimetic plasmepsin inhibitors

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