title: Potent inhibitor scaffold against Trypanosoma cruzi trans-sialidase.
abstract: The protozoan Trypanosoma cruzi, the causative agent of Chagas' disease, can infect the heart, causing cardiac arrest frequently followed by death. To treat this disease, a potential molecular drug target is T. cruzi trans-sialidase (TcTS). However, inhibitors found to date are not strong enough to serve as a lead scaffold; most inhibitors reported thus far are derivatives of the substrate sialic acid or a transition state analogue known as 2,3-dehydro-3-deoxy-N-acetylneuraminic acid (DANA) with an IC(50) value of more than hundreds of micromolar. Since natural products are highly stereodiversified and often provide highly specific biological activity, we screened a natural product library for inhibitors of TcTS and identified promising flavonoid and anthraquinone derivatives. A structure-activity relationship (SAR) analysis of the flavonoids revealed that apigenin had the minimal and sufficient structure for inhibition. Intriguingly, the compound has been reported to possess trypanocidal activity. An SAR analysis of anthraquinones showed that 6-chloro-9,10-dihydro-4,5,7-trihydroxy-9,10-dioxo-2-anthracenecarboxylic acid had the strongest inhibitory activity ever found against TcTS. Moreover, its inhibitory activity appeared to be specific to TcTS. These compounds may serve as potent lead chemotherapeutic scaffolds against Chagas' disease.
authors.affiliation: Laboratory of Advanced Chemical Biology, Graduate School of Life Science, Frontier Research Center for Post-Genome, Science and Technology, Hokkaido University, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Arioka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Rie
authors.initials: R
authors.lastname: Uematsu
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togame
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hinou
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D011994:Recombinant Proteins; C069715:trans-sialidase; D009439:Neuraminidase