Abstract
Background
Target repurposing utilizes knowledge of "druggable" targets obtained in one organism and exploits this information to pursue new potential drug targets in other organisms. Here we describe such studies to evaluate whether inhibitors targeting the kinase domain of the mammalian Target of Rapamycin (mTOR) and human phosphoinositide-3-kinases (PI3Ks) show promise against the kinetoplastid parasites Trypanosoma brucei, T. cruzi, Leishmania major, and L. donovani. The genomes of trypanosomatids encode at least 12 proteins belonging to the PI3K protein superfamily, some of which are unique to parasites. Moreover, the shared PI3Ks differ greatly in sequence from those of the human host, thereby providing opportunities for selective inhibition.
Methodology/Principal Findings
We focused on 8 inhibitors targeting mTOR and/or PI3Ks selected from various stages of pre-clinical and clinical development, and tested them against in vitro parasite cultures and in vivo models of infection. Several inhibitors showed micromolar or better efficacy against these organisms in culture. One compound, NVP-BEZ235, displayed sub-nanomolar potency, efficacy against cultured parasites, and an ability to clear parasitemia in an animal model of T. brucei rhodesiense infection.
Conclusions/Significance
These studies strongly suggest that mammalian PI3/TOR kinase inhibitors are a productive starting point for anti-trypanosomal drug discovery. Our data suggest that NVP-BEZ235, an advanced clinical candidate against solid tumors, merits further investigation as an agent for treating African sleeping sickness.
Keywords
drug targets, mammalian Target of Rapamycin (mTOR), human phosphoinositide-3-kinases (PI3Ks), kinetoplastid parasites
Subject Categories
Drug targeting, Protein-tyrosine kinase - Inhibitors
Disciplines
Chemical and Pharmacologic Phenomena | Epidemiology | Medical Pharmacology | Parasitic Diseases
Publisher
Public Library of Science
Publication Date
8-23-2011
Rights Information
© 2011 Diaz-Gonzalez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Rights Holder
Diaz-Gonzalez, et al.
Permanent URL
Recommended Citation
Diaz-Gonzalez, Rosario; Kuhlmann, F. Matthew; Galan-Rodriguez, Cristina; Madeira da Silva, Luciana; Karver, Caitlin E.; Rodriguez, Ana; Beverley, Stephen M.; Navarro, Miguel; and Pollastri, Michael P., "The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing" (2011). Chemistry and Chemical Biology Faculty Publications. Paper 1. http://hdl.handle.net/2047/d20001016
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Notes
Originally published as: Diaz-Gonzalez R, Kuhlmann FM, Galan-Rodriguez C, da Silva LM, Saldivia M, et al. (2011) The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing. PLoS Negl Trop Dis 5(8): e1297. doi:10.1371/journal.pntd.0001297
This work was supported in part by Northeastern University, NIH R01AI082577 (MPP, CEK), T32-A1007172 (FMK), AI029646 (FMK, LMS, SMB), the Spanish Ministerio de Ciencia e Innovación grant (SAF2009-07587) and Red de Investigacion de Centros de Enfermedades Tropicales Grant (RD06/0021/0010) (MN). The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript.