Antileishmanial drug development

Exploitation of parasite heme dependency

Jane Xu Kelly, Marina V. Ignatushchenko, H. G. Bouwer, David H. Peyton, David J. Hinrichs, R. W. Winter, Michael Riscoe

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-ω-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalMolecular and Biochemical Parasitology
Volume126
Issue number1
DOIs
StatePublished - Jan 2003

Fingerprint

Heme
Parasites
Xanthones
Pharmaceutical Preparations
Leishmania
Leishmania mexicana
Pentamidine
Antiparasitic Agents
Nutritional Requirements
Biosynthetic Pathways
Porphyrins
Electron Transport
Enzymes
Proteins

Keywords

  • Chemotherapy
  • Drug design
  • Heme
  • Leishmania
  • Leishmania mexicana
  • Pentamidine
  • Persian Gulf War
  • Porphyrin
  • Xanthone

ASJC Scopus subject areas

  • Molecular Biology
  • Parasitology

Cite this

Kelly, J. X., Ignatushchenko, M. V., Bouwer, H. G., Peyton, D. H., Hinrichs, D. J., Winter, R. W., & Riscoe, M. (2003). Antileishmanial drug development: Exploitation of parasite heme dependency. Molecular and Biochemical Parasitology, 126(1), 43-49. https://doi.org/10.1016/S0166-6851(02)00248-7

Antileishmanial drug development : Exploitation of parasite heme dependency. / Kelly, Jane Xu; Ignatushchenko, Marina V.; Bouwer, H. G.; Peyton, David H.; Hinrichs, David J.; Winter, R. W.; Riscoe, Michael.

In: Molecular and Biochemical Parasitology, Vol. 126, No. 1, 01.2003, p. 43-49.

Research output: Contribution to journalArticle

Kelly, JX, Ignatushchenko, MV, Bouwer, HG, Peyton, DH, Hinrichs, DJ, Winter, RW & Riscoe, M 2003, 'Antileishmanial drug development: Exploitation of parasite heme dependency', Molecular and Biochemical Parasitology, vol. 126, no. 1, pp. 43-49. https://doi.org/10.1016/S0166-6851(02)00248-7
Kelly JX, Ignatushchenko MV, Bouwer HG, Peyton DH, Hinrichs DJ, Winter RW et al. Antileishmanial drug development: Exploitation of parasite heme dependency. Molecular and Biochemical Parasitology. 2003 Jan;126(1):43-49. https://doi.org/10.1016/S0166-6851(02)00248-7
Kelly, Jane Xu ; Ignatushchenko, Marina V. ; Bouwer, H. G. ; Peyton, David H. ; Hinrichs, David J. ; Winter, R. W. ; Riscoe, Michael. / Antileishmanial drug development : Exploitation of parasite heme dependency. In: Molecular and Biochemical Parasitology. 2003 ; Vol. 126, No. 1. pp. 43-49.
@article{f1b6b89b13a04a098af4481fd4fb6cc4,
title = "Antileishmanial drug development: Exploitation of parasite heme dependency",
abstract = "A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-ω-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.",
keywords = "Chemotherapy, Drug design, Heme, Leishmania, Leishmania mexicana, Pentamidine, Persian Gulf War, Porphyrin, Xanthone",
author = "Kelly, {Jane Xu} and Ignatushchenko, {Marina V.} and Bouwer, {H. G.} and Peyton, {David H.} and Hinrichs, {David J.} and Winter, {R. W.} and Michael Riscoe",
year = "2003",
month = "1",
doi = "10.1016/S0166-6851(02)00248-7",
language = "English (US)",
volume = "126",
pages = "43--49",
journal = "Molecular and Biochemical Parasitology",
issn = "0166-6851",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Antileishmanial drug development

T2 - Exploitation of parasite heme dependency

AU - Kelly, Jane Xu

AU - Ignatushchenko, Marina V.

AU - Bouwer, H. G.

AU - Peyton, David H.

AU - Hinrichs, David J.

AU - Winter, R. W.

AU - Riscoe, Michael

PY - 2003/1

Y1 - 2003/1

N2 - A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-ω-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.

AB - A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-ω-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.

KW - Chemotherapy

KW - Drug design

KW - Heme

KW - Leishmania

KW - Leishmania mexicana

KW - Pentamidine

KW - Persian Gulf War

KW - Porphyrin

KW - Xanthone

UR - http://www.scopus.com/inward/record.url?scp=12244297737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12244297737&partnerID=8YFLogxK

U2 - 10.1016/S0166-6851(02)00248-7

DO - 10.1016/S0166-6851(02)00248-7

M3 - Article

VL - 126

SP - 43

EP - 49

JO - Molecular and Biochemical Parasitology

JF - Molecular and Biochemical Parasitology

SN - 0166-6851

IS - 1

ER -