Proteasome inhibitors block development of Plasmodium spp.

Soren M. Gantt, Joon Mo Myung, Marcelo R S Briones, Wei Dong Li, E. J. Corey, Satoshi Omura, Victor Nussenzweig, Photini Sinnis

Research output: Contribution to journalArticle

Abstract

Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.

Original languageEnglish (US)
Pages (from-to)2731-2738
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume42
Issue number10
StatePublished - Oct 1998
Externally publishedYes

Fingerprint

Proteasome Inhibitors
Plasmodium
Plasmodium berghei
Parasites
Proteasome Endopeptidase Complex
Cell Cycle
Entamoeba
Trypanosoma
Sporozoites
Parasitemia
Eukaryotic Cells
Pharmaceutical Preparations
Malaria
Transcription Factors
lactacystin
DNA
Proteins

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Gantt, S. M., Myung, J. M., Briones, M. R. S., Li, W. D., Corey, E. J., Omura, S., ... Sinnis, P. (1998). Proteasome inhibitors block development of Plasmodium spp. Antimicrobial Agents and Chemotherapy, 42(10), 2731-2738.

Proteasome inhibitors block development of Plasmodium spp. / Gantt, Soren M.; Myung, Joon Mo; Briones, Marcelo R S; Li, Wei Dong; Corey, E. J.; Omura, Satoshi; Nussenzweig, Victor; Sinnis, Photini.

In: Antimicrobial Agents and Chemotherapy, Vol. 42, No. 10, 10.1998, p. 2731-2738.

Research output: Contribution to journalArticle

Gantt, SM, Myung, JM, Briones, MRS, Li, WD, Corey, EJ, Omura, S, Nussenzweig, V & Sinnis, P 1998, 'Proteasome inhibitors block development of Plasmodium spp.', Antimicrobial Agents and Chemotherapy, vol. 42, no. 10, pp. 2731-2738.
Gantt SM, Myung JM, Briones MRS, Li WD, Corey EJ, Omura S et al. Proteasome inhibitors block development of Plasmodium spp. Antimicrobial Agents and Chemotherapy. 1998 Oct;42(10):2731-2738.
Gantt, Soren M. ; Myung, Joon Mo ; Briones, Marcelo R S ; Li, Wei Dong ; Corey, E. J. ; Omura, Satoshi ; Nussenzweig, Victor ; Sinnis, Photini. / Proteasome inhibitors block development of Plasmodium spp. In: Antimicrobial Agents and Chemotherapy. 1998 ; Vol. 42, No. 10. pp. 2731-2738.
@article{136e51dd486545e6965db8255489ce94,
title = "Proteasome inhibitors block development of Plasmodium spp.",
abstract = "Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.",
author = "Gantt, {Soren M.} and Myung, {Joon Mo} and Briones, {Marcelo R S} and Li, {Wei Dong} and Corey, {E. J.} and Satoshi Omura and Victor Nussenzweig and Photini Sinnis",
year = "1998",
month = "10",
language = "English (US)",
volume = "42",
pages = "2731--2738",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "10",

}

TY - JOUR

T1 - Proteasome inhibitors block development of Plasmodium spp.

AU - Gantt, Soren M.

AU - Myung, Joon Mo

AU - Briones, Marcelo R S

AU - Li, Wei Dong

AU - Corey, E. J.

AU - Omura, Satoshi

AU - Nussenzweig, Victor

AU - Sinnis, Photini

PY - 1998/10

Y1 - 1998/10

N2 - Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.

AB - Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.

UR - http://www.scopus.com/inward/record.url?scp=0002709230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0002709230&partnerID=8YFLogxK

M3 - Article

C2 - 9756786

AN - SCOPUS:0002709230

VL - 42

SP - 2731

EP - 2738

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 10

ER -