Solid-phase combinatorial synthesis of a lysyl-tRNA synthetase (LysRS) inhibitory library.
The solid-phase combinatorial synthesis of a new library with potential inhibitory activity against the cytoplasmic lysyl-tRNA synthetase (LysRS) isoform of Trypanosoma brucei is described. The library has been specifically designed to mimic the lysyl adenylate complex. The design was carried out by dividing the complex into four modular parts. Proline derivatives (cis-gamma-amino-L-proline or trans-gamma-hydroxy-L-proline) were chosen as central scaffolds. After primary screening, three compounds of the library caused in vitro inhibition of the tRNA aminoacylation reaction in the low micromolar range.
Farrera-Sinfreu
Josep
J
Institute for Research in Biomedicine and Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, Josep Samitier 1, 08028-Barcelona, Spain.
Español
Yaiza
Y
Geslain
Renaud
R
Guitart
Tanit
T
Albericio
Fernando
F
Ribas de Pouplana
Lluís
L
Royo
Miriam
M
D049148:Aminoacylation / Q000187:drug effects; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D008250:Lysine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D000981:Antiprotozoal Agents; D011392:Proline; D008250:Lysine-tRNA Ligase