This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ponte-Sucre, A.
Right arrow Articles by Moll, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ponte-Sucre, A.
Right arrow Articles by Moll, H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2006, p. 2439-2447, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01430-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Alicia Ponte-Sucre,1,3 Radim Vicik,2 Martina Schultheis,1 Tanja Schirmeister,2 and Heidrun Moll1*

Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany,1 Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany,2 Laboratory of Molecular Physiology, Universidad Central de Venezuela, Apdo. 68256, Caracas 1062-A, Venezuela3

Received 7 November 2005/ Returned for modification 18 November 2005/ Accepted 27 April 2006

Chemotherapy of leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis. Leishmania cysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating leishmaniasis. Herein we demonstrate that the cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the infection rate of peritoneal macrophages at concentrations 8- to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage infection rate. Notably, treatment with the compounds alone modulated the cytokine secretion of infected macrophages, with increased levels of interleukin-12 and tumor necrosis factor alpha. Furthermore, the decreased infection rate in the presence of compound 13b correlated with increased nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective antiparasitic effects.

* Corresponding author. Mailing address: Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany. Phone: 49 0931 312627. Fax: 49 0931 312578. E-mail: heidrun.moll{at}mail.uni-wuerzburg.de.

Antimicrobial Agents and Chemotherapy, July 2006, p. 2439-2447, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.01430-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bryson, K., Besteiro, S., McGachy, H. A., Coombs, G. H., Mottram, J. C., Alexander, J. (2009). Overexpression of the Natural Inhibitor of Cysteine Peptidases in Leishmania mexicana Leads to Reduced Virulence and a Th1 Response. Infect. Immun. 77: 2971-2978 [Abstract] [Full Text]  
  • Ponte-Sucre, A., Faber, J. H., Gulder, T., Kajahn, I., Pedersen, S. E. H., Schultheis, M., Bringmann, G., Moll, H. (2007). Activities of Naphthylisoquinoline Alkaloids and Synthetic Analogs against Leishmania major. Antimicrob. Agents Chemother. 51: 188-194 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»