Exploring Leishmania major Inositol Phosphorylceramide Synthase (LmjIPCS): Insights into the ceramide binding domain

Mina, John G.; Mosely, Jackie A.; Ali, Hayder Z.; Denny, Paul W.; Steel, Patrick G.

doi:10.1039/c0ob00871k

Cited by 38 publications

(46 citation statements)

References 56 publications

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“…The acetonide group present in 11a was then deprotected with CSA in methanol to afford 8 with 90% yield. 39 Similarly, Clavaminol C (2) was prepared from 1 under the same reaction conditions as followed for the preparation of 5 from 8 (Scheme 3). …”

Section: Resultsmentioning

confidence: 99%

General synthetic strategy for clavaminols A, C and H

Thirupathi¹,

Bharath²,

Mohapatra³

2015

Arkivoc

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Dedicated to Dr. J. S. Yadav on the occasion of his 65th birthday and in appreciation of his outstanding contributions to synthetic organic chemistry DOI: http://dx.doi.org/10.3998/ark.5550190.p009.281 Abstract A general and efficient synthetic strategy has been developed for the total syntheses of clavaminols A, C and H in 5 to 7 steps starting from (R)-Garners aldehyde following Grignard reaction, Corey-Bakshi-Shibata asymmetric reduction and selective acetylation as key steps with 42 to 59% overall yields, respectively.

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Section: Resultsmentioning

confidence: 99%

General synthetic strategy for clavaminols A, C and H

Thirupathi¹,

Bharath²,

Mohapatra³

2015

Arkivoc

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“…The continuous murine macrophage cell line RAW264.7 was maintained in DMEM (Gibco-BRL) with 10% FBS, at 37°C and 5% CO 2 . The cytoxicity of myriocin (Sigma Aldrich) was established using the AlamarBlue (Invitrogen) assay according to manufacturer's protocol and as previously [21, 22]. The efficacy of myriocin was confirmed using a yeast diffusion assay [23].…”

Section: Methodsmentioning

confidence: 99%

Endocytosis and Sphingolipid Scavenging inLeishmania mexicanaAmastigotes

Ali

Harding

Denny

2012

Biochemistry Research International

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Leishmania species are the causative agents of the leishmaniases, a spectrum of neglected tropical diseases. Amastigote stage parasites exist within macrophages and scavenge host factors for survival, for example, Leishmania species utilise host sphingolipid for synthesis of complex sphingolipid. In this study L. mexicana endocytosis was shown to be significantly upregulated in amastigotes, indicating that sphingolipid scavenging may be enhanced. However, inhibition of host sphingolipid biosynthesis had no significant effect on amastigote proliferation within a macrophage cell line. In addition, infection itself did not directly influence host biosynthesis. Notably, in contrast to L. major, L. mexicana amastigotes are indicated to possess a complete biosynthetic pathway suggesting that scavenged sphingolipids may be nonessential for proliferation. This suggested that Old and New World species differ in their interactions with the macrophage host. This will need to be considered when targeting the Leishmania sphingolipid biosynthetic pathway with novel therapeutics.

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“…Given this, partially purified microsomal extracts from complemented yeast have been used to develop a 96-well plate-based enzyme that was used to define the mode of action and substrate requirements of the protozoan enzyme. [42][43] This assay platform is, however, unsuitable for true HTS due to its complexity, requiring ion exchange to separate fluorescently tagged lipid substrate from fluorescently tagged lipid product. To facilitate high-content HTS, IPC synthase (AUR1p) 44 null S. cerevisiae complemented with the L. major orthologue has been formatted into a robust 1536-well assay platform and used to screen the GSK compound collection, identifying selective submicromolar inhibitors of the parasite enzyme 45 (https://www.openlabfoundation.org).…”

Section: Substitutionmentioning

confidence: 99%

Yeast as a Potential Vehicle for Neglected Tropical Disease Drug Discovery

Denny

Steel

2015

SLAS Discovery

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High-throughput screening (HTS) efforts for neglected tropical disease (NTD) drug discovery have recently received increased attention because several initiatives have begun to attempt to reduce the deficit in new and clinically acceptable therapies for this spectrum of infectious diseases. HTS primarily uses two basic approaches, cell-based and in vitro target-directed screening. Both of these approaches have problems; for example, cell-based screening does not reveal the target or targets that are hit, whereas in vitro methodologies lack a cellular context. Furthermore, both can be technically challenging, expensive, and difficult to miniaturize for ultra-HTS [(u)HTS]. The application of yeast-based systems may overcome some of these problems and offer a cost-effective platform for target-directed screening within a eukaryotic cell context. Here, we review the advantages and limitations of the technologies that may be used in yeast cell-based, target-directed screening protocols, and we discuss how these are beginning to be used in NTD drug discovery.

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Exploring Leishmania major Inositol Phosphorylceramide Synthase (LmjIPCS): Insights into the ceramide binding domain

Cited by 38 publications

References 56 publications

General synthetic strategy for clavaminols A, C and H

General synthetic strategy for clavaminols A, C and H

Endocytosis and Sphingolipid Scavenging inLeishmania mexicanaAmastigotes

Yeast as a Potential Vehicle for Neglected Tropical Disease Drug Discovery

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