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HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites

White, Rhian Ellen, Powell, David J. and Berry, Colin 2011. HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites. The FASEB Journal 25 (5) , pp. 1729-1736. 10.1096/fj.10-178947

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Abstract

HIV proteinase inhibitors reduce the levels of Leishmania parasites in vivo and in vitro, but their biochemical target is unknown. We have identified an ortholog of the yeast Ddi1 protein as the only member of the aspartic proteinase family in Leishmania parasites, and in this study we investigate this protein as a potential target for the drugs. To date, no enzyme assay has been developed for the Ddi1 proteins, but Saccharomyces cerevisiae lacking the DDI1 gene secrete high levels of protein into the medium. We developed an assay in which these knockout yeast were functionally complemented to low secretion by introduction of genes encoding Ddi1 orthologs from Leishmania major or humans. Plasmid alone controls gave no complementation. Treatment of the Ddi1 transformants with HIV proteinase inhibitors showed differential effects dependent on the origin of the Ddi1. Dose responses allowed calculation of IC50 values; e.g., for nelfinavir, of 3.4 μM (human Ddi1) and 0.44 μM (Leishmania Ddi1). IC50 values with Leishmania constructs mirror the potency of inhibitors against parasites. Our results show that Ddi1 proteins are targets of HIV proteinase inhibitors and indicates the Leishmania Ddi1 as the likely target for these drugs and a potential target for antiparasitic therapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RB Pathology
Publisher: Federation of American Societies of Experimental Biology
ISSN: 0892-6638
Last Modified: 04 Jun 2017 03:33
URI: http://orca.cf.ac.uk/id/eprint/22767

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