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

05 April 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The standard drug for treatment of the neglected disease Schistosomiasis is Praziquantel, and the possible emergence of resistance to this treatment makes the research on novel therapeutic agents necessary and urgent. To this end, the targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to strong effects of human Sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as potential therapeutic targets. In vitro testing of synthetic substrates of SmSirt2 and kinetic experiments on a myristoylated peptide newly demonstrated lysine long chain deacylation as an intrinsic SmSirt2 activity in addition to the known deacetylation. 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.

Keywords

Epigenetics
Sirtuins
Schistosoma mansoni

Supplementary materials

Title
Description
Actions
Title
smSirt2 manuscript final
Description
Actions
Title
supporting info HPLC smSirt2
Description
Actions
Title
Supporting informations smSirt2
Description
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.