Development and characterisation of SMURF2-targeting modifiers

Autor: Dhanoop Manikoth Ayyathan, Gal Levy-Cohen, Moran Shubely, Sandy Boutros-Suleiman, Veronica Lepechkin-Zilbermintz, Michael Shokhen, Amnon Albeck, Arie Gruzman, Michael Blank
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 401-409 (2021)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2020.1871337
Popis: The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2’s autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both in vitro and in cellulo at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or SMURF2-specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje