Leishmania major protein disulfide isomerase as a drug target: enzymatic and functional characterization

Noureddine Ben Khalaf, Géraldine De Muylder, Hechmi Louzir, James McKerrow, Mehdi Chenik

Research output: Contribution to journalA1: Web of Science-article

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 EC(50) values of 39 μM. These results suggest that LmPDI may constitute an interesting target for the development of new anti-Leishmania drugs.

Original languageEnglish
JournalParasitology Research
Volume110
Issue number5
Pages (from-to)1911-1917
Number of pages7
ISSN0932-0113
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Animals
  • Antiprotozoal Agents
  • Bacitracin
  • Cell Line
  • Disulfides
  • Enzyme Inhibitors
  • Humans
  • Leishmania major
  • Monocytes
  • Protein Disulfide-Isomerases
  • Protein Folding
  • Ribostamycin
  • Virulence Factors
  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.

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