Potent inhibitor scaffold against Trypanosoma cruzi trans-sialidase

Bioorganic & Medicinal Chemistry
Shingo AriokaShin-Ichiro Nishimura

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 ...Continue Reading

References

Dec 1, 1992·Glycobiology·F VandekerckhoveV Nussenzweig
Oct 1, 1992·Clinical Microbiology Reviews·H B TanowitzM Wittner
Jun 1, 1985·Molecular and Biochemical Parasitology·J O PreviatoL Mendonça-Previato
Mar 1, 1980·The American Journal of Tropical Medicine and Hygiene·G A SchmuñisJ M Peralta
Feb 28, 1994·Biochemical and Biophysical Research Communications·S NishimuraY C Lee
Nov 7, 1996·Nature·G L Verdine
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Jan 28, 2003·Journal of Chemical Information and Computer Sciences·Miklos Feher, Jonathan M Schmidt
Jul 25, 2003·Journal of Medicinal Chemistry·Ali J RyanChun-wa Chung
Jul 26, 2003·Journal of Natural Products·David J NewmanKenneth M Snader
Oct 29, 2003·Trends in Parasitology·Julio A Urbina, Roberto Docampo
Apr 9, 2004·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·E C SchinorD A Dias
Jun 1, 1993·Parasitology Today·S Schenkman, D Eichinger
Dec 14, 2004·Journal of Molecular Biology·Gastón ParisAlberto Carlos C Frasch
Jul 16, 2005·Science·Najib M El-SayedBjörn Andersson
Sep 24, 2005·Combinatorial Chemistry & High Throughput Screening·George G Harrigan, Gilles H Goetz
Jan 13, 2006·Nature Chemical Biology·Brian Y FengBrian K Shoichet
Oct 17, 2006·Parasitology Today·S Tomlinson, J Raper
Dec 28, 2006·Nature Protocols·Brian Y Feng, Brian K Shoichet
Apr 5, 2007·Nature Protocols·Ai-Sheng XiongYi Li
Sep 22, 2007·Science·Elodie GhedinAlan L Scott
Feb 16, 2008·Drug Discovery Today·João NeresKenneth T Douglas
Aug 13, 2008·Antimicrobial Agents and Chemotherapy·Keiko HataTaeko Miyagi
Mar 14, 2009·Journal of Medicinal Chemistry·Kristin E D CoanBrian K Shoichet
Aug 1, 2009·Journal of Biomolecular Screening·Adam B ShapiroThomas A Keating
Sep 26, 2009·Chembiochem : a European Journal of Chemical Biology·Jin Hyo KimStephen G Withers

❮ Previous
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Citations

Mar 21, 2012·Infection and Immunity·Luis Miguel De Pablos, Antonio Osuna
Jul 21, 2010·Glycoconjugate Journal·M Eugenia GiorgiRosa M de Lederkremer
Oct 23, 2013·Future Medicinal Chemistry·Bill R Miller, Adrian E Roitberg
Jul 4, 2012·Cellular Microbiology·Sergio S C Dc-Rubin, Sergio Schenkman
Dec 31, 2014·The Korean Journal of Parasitology·Rosan Barbosa de MatosSilvia Lima Costa
Feb 1, 2017·Journal of Drug Targeting·Muhammad KashifGildardo Rivera
Nov 18, 2017·Journal of Bioenergetics and Biomembranes·Robson Xavier FariaLeandro Rocha
Oct 1, 2011·Chembiochem : a European Journal of Chemical Biology·Roland Schauer, Johannis P Kamerling
Dec 13, 2012·Chemistry : a European Journal·Hirokazu KaiShin-Ichiro Nishimura
Dec 6, 2018·Chemistry : a European Journal·Yoan BrissonnetSébastien G Gouin
Aug 24, 2019·Phytotherapy Research : PTR·Pone Kamdem Boniface, Elizabeth Igne Ferreira
Feb 10, 2011·Chemistry, an Asian Journal·Hiroshi HinouShin-Ichiro Nishimura
Jan 31, 2020·Frontiers in Cellular and Infection Microbiology·Yan-Hua Wang
May 13, 2014·Acta Crystallographica. Section D, Biological Crystallography·Youngjin LeeSoo Hyun Eom
Aug 18, 2020·International Journal of Biological Macromolecules·Santanu Sasidharan, Prakash Saudagar
Apr 19, 2019·ACS Medicinal Chemistry Letters·Chiara BorsariMaria Paola Costi

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