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Leishmania major protein disulfide isomerase as a drug target

Enzymatic and functional characterization

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Abstract

Leishmaniasis is a major health problem worldwide and tools available for their control are limited. Effective vaccines are still lacking, drugs are toxic and expensive, and parasites develop resistance to chemotherapy. In this context, new antimicrobials are urgently needed to control the disease in both human and animal. Here, we report the enzymatic and functional characterization of a Leishmania virulence factor, Leishmania major Protein disulfide isomerase (LmPDI) that could constitute a potential drug target. LmPDI possesses domain structure organization similar to other PDI family members (a, a′, b, b′ and c domains), and it displays the three enzymatic and functional activities specific of PDI family members: isomerase, reductase and chaperone. These results suggest that LmPDI plays a key role in assisting Leishmania protein folding via its capacity to catalyze formation, breakage, and rearrangement of disulfide bonds in nascent polypeptides. Moreover, Bacitracin, a reductase activity inhibitor, and Ribostamycin, a chaperone activity inhibitor, were tested in LmPDI enzymatic assays and versus Leishmania promastigote in vitro cultures and Leishmania amastigote multiplication inside infected THP-1-derived macrophages. Bacitracin inhibited both isomerase and reductase activities, while Ribostamycin had no effect on the chaperone activity. Interestingly, Bacitracin blocked in vitro promastigote growth as well as amastigote multiplication inside macrophages with EC50 values of 39 μM. These results suggest that LmPDI may constitute an interesting target for the development of new anti-Leishmania drugs.

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Abbreviations

LmPDI:

Leishmania major protein disulfide isomerase

PDI:

Protein disulfide isomerase

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Acknowledgements

This work was supported by the Sandler Foundation. We thank Farah Boubaker and Sima Drini for research assistance and Yosser Ben Achour Chenik for English proofreading.

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Authors and Affiliations

  1. Laboratory of Immunopathology Vaccinology and Molecular Genetics (LIVGM), Institut Pasteur de Tunis, 13, Place Pasteur, 1002, Tunis-Belvédère, Tunisia

    Noureddine Ben Khalaf, Hechmi Louzir & Mehdi Chenik

  2. Sandler Center for Drug Discovery, University of California, 1700 4th Street, QB3/Byers Hall, Room 508, Mission Bay Campus, San Francisco, CA, 94158-2330, USA

    Géraldine De Muylder & James McKerrow

  3. Laboratory of Medical Parasitology, Biotechnology and Biomolecules, Institut Pasteur de Tunis, 13, Place Pasteur, 1002, Tunis-Belvédère, Tunisia

    Noureddine Ben Khalaf & Mehdi Chenik

Authors
  1. Noureddine Ben Khalaf
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  2. Géraldine De Muylder
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  3. Hechmi Louzir
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  4. James McKerrow
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  5. Mehdi Chenik
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Correspondence to Mehdi Chenik.

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Ben Khalaf, N., De Muylder, G., Louzir, H. et al. Leishmania major protein disulfide isomerase as a drug target. Parasitol Res 110, 1911–1917 (2012). https://doi.org/10.1007/s00436-011-2717-5

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  • DOI: https://doi.org/10.1007/s00436-011-2717-5

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