Download MendeleyCryptosporidium and Toxoplasma Parasites are Inhibited by a Benzoxaborole Targeting Leucyl-tRNA Synthetase.
Palencia, A., Liu, R., Lukarska, M., Gut, J., Bougdour, A., Touquet, B., Wang, E., Li, X., Alley, M.R.K., Freund, Y.R., Rosenthal, P.J., Hakimi, M., Cusack, S.(2016) Antimicrob Agents Chemother 60: 5817
- PubMed: 27431220
- DOI: https://doi.org/10.1128/AAC.00873-16
- Primary Citation of Related Structures:
5FOG, 5FOL, 5FOM, 5FON - PubMed Abstract:
The apicomplexan parasites Cryptosporidium and Toxoplasma are serious threats to human health. Cryptosporidiosis is a severe diarrheal disease in malnourished children and immunocompromised individuals, with the only FDA-approved drug treatment currently being nitazoxanide. The existing therapies for toxoplasmosis, an important pathology in immunocompromised individuals and pregnant women, also have serious limitations. With the aim of developing alternative therapeutic options to address these health problems, we tested a number of benzoxaboroles, boron-containing compounds shown to be active against various infectious agents, for inhibition of the growth of Cryptosporidium parasites in mammalian cells. A 3-aminomethyl benzoxaborole, AN6426, with activity in the micromolar range and with activity comparable to that of nitazoxanide, was identified and further characterized using biophysical measurements of affinity and crystal structures of complexes with the editing domain of Cryptosporidium leucyl-tRNA synthetase (LeuRS). The same compound was shown to be active against Toxoplasma parasites, with the activity being enhanced in the presence of norvaline, an amino acid that can be mischarged by LeuRS. Our observations are consistent with AN6426 inhibiting protein synthesis in both Cryptosporidium and Toxoplasma by forming a covalent adduct with tRNA(Leu) in the LeuRS editing active site and suggest that further exploitation of the benzoxaborole scaffold is a valid strategy to develop novel, much needed antiparasitic agents.
Organizational Affiliation:
European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France, and University Grenoble Alpes-CNRS-EMBL International Unit (UMI 3265) for Virus Host-Cell Interactions, UMI 3265, Grenoble, France Institute for Advanced Biosciences, Team Host-Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France [email protected] [email protected].
