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Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma Mansoni (SmSirt2)

preprint
revised on 02.08.2019 and posted on 02.08.2019 by Daria Monaldi, Dante Rotili, Julien Lancelot, Martin Marek, Nathalie Wössner, Alessia Lucidi, Daniela Tomaselli, Elizabeth Ramos-Morales, Christophe Romier, Raymond J. Pierce, Antonello Mai, Manfred Jung
The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary. Targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to the strong effects of human Sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as therapeutic targets. In vitro testing of synthetic substrates of S. mansoni Sirtuin 2 (SmSirt2) and kinetic experiments on a myristoylated peptide demonstrated lysine long chain deacylation as an intrinsic SmSirt2 activity for the first time. Focused in vitro screening of the GSK Kinetobox library and structure-activity relationships (SAR) of identified hits, led to the first SmSirt2 inhibitors with activity in the low micromolar range. Several SmSirt2 inhibitors showed potency against both larval schistosomes (viability) and adult worms (pairing, egg laying) in culture without general toxicity to human cancer cells.

History

Email Address of Submitting Author

manfred.jung@pharmazie.uni-freiburg.de

Institution

University of Freiburg

Country

Germany

ORCID For Submitting Author

0000-0002-6361-7716

Declaration of Conflict of Interest

No conflict of interest

Version Notes

1.0 Original Submission 2.0 Revised version (hSirt13 selectivity, kinetic data on lysine substrates added)

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