The universally essential enzyme prolyl-tRNA synthetase (ProRS) has recently been identified as a molecular target for the drug halofuginone, which is derived from natural products with anti-malarial activity. Halofuginone exhibits a conserved mode of binding to both plasmodium and human ProRS as shown by crystal structures of the respective drug:enzyme complexes. We have shown that halofuginone is also blocks growth and encystation of Giardia in culture with an EC50 approximately equal to that of the current front line anti-giardiasis drug metronidazole. Nevertheless the active site of ProRS from Giardia and from Trichomonas species differs significantly from that of the human and plasmodium homologs, as we have shown by sequence analysis and by determining a Giardia ProRS crystal structure. This strongly suggests that suitable modification of halofuginone will both increase its potency and its specificity of action against Giardia and Trichomonas parasites relative to the human host. We will evaluate such compounds for activity in suppressing parasite growth, cell attachment, or encystation. A primary goal is to use SAR-guided synthetic chemistry to develop compounds that are orally bioavailable, sufficiently potent, lack toxicity, and cure animal models of Giardia infection. By the end of this project we expect to have lead compounds for evaluation as new drugs against giardiasis and trichomoniasis.
This project will identify and develop leads for a new drug to treat giardiasis, a disease caused by parasitic protozoa commonly transmitted by contaminated food or unpurified water, and trichomoniasis, a sexually transmitted disease caused also by parasitic protozoa. The starting point is an existing drug derived from a natural produce with anti-malarial activity. We will design and characterize compounds with improved potency against two different diseases and are expected to show reduced side-effects in humans.
| Hennessey, Kelly M; Rogiers, Ilse C; Shih, Han-Wei et al. (2018) Screening of the Pathogen Box for inhibitors with dual efficacy against Giardia lamblia and Cryptosporidium parvum. PLoS Negl Trop Dis 12:e0006673 |
