PDBsum entry 5fog

Lyase

PDB id: 5fog

Contents

Protein chains

279 a.a.

Ligands

VRT ×4

EDO ×4

Metals

__K ×2

Waters ×370

References listed in PDB file

Key reference

• Title: Cryptosporidium and toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-Trna synthetase.
• Authors: A.Palencia, R.J.Liu, M.Lukarska, J.Gut, A.Bougdour, B.Touquet, E.D.Wang, X.Li, M.R.Alley, Y.R.Freund, P.J.Rosenthal, M.A.Hakimi, S.Cusack.
• Ref.: Antimicrob Agents Chemother, 2016, 60, 5817-5827. [DOI no: 10.1128/AAC.00873-16]
• PubMed id: 27431220

Note: In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above have been manually determined.

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.