Bertinaria, Massimo

Boscaro, Valentina

Gallicchio, Margherita

Gastaldi, Simone

Giorgis, Marta

Marini, Elisabetta

Marino, Marco

English

Institutional Research Information System University of Turin

16 October 2023AperTO - Archivio Istituzionale Open Access dell'Università di TorinoOriginal Citation:Pharmacological characterization of new NLRP3 inflammasome inhibitors.Terms of use:Open Access(Article begins on next page)Anyone can freely access the full text of works made available as "Open Access". Works made availableunder a Creative Commons license can be used according to the terms and conditions of said license. Useof all other works requires consent of the right holder (author or publisher) if not exempted from copyrightprotection by the applicable law.Availability:This is the author's manuscriptThis version is available http://hdl.handle.net/2318/1755487 since 2022-01-19T10:30:58Z Pharmacological characterization of new NLRP3 inflammasome inhibitors.  Valentina Boscaro, Simone Gastaldi, Marco Marino, Marta Giorgis, Elisabetta Marini, Massimo Bertinaria and Margherita Gallicchio Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino  Introduction  The NLR family protein NLRP3 is an intracellular signalling molecule activated by many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 controls the formation of the catalytically active protease, caspase-1, leading to cleavage of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 to their active forms and to a type of inflammatory cell death known as pyroptosis. NLRP3 plays a critical role in the inflammatory process and it has been implicated in the pathogenesis of metabolic disorders such as type 2 diabetes, atherosclerosis and obesity. NLRP3 has also been involved in diseases of the central nervous system and lung, liver, kidney diseases and aging (Coll et al. Nat Med. 2015, 21(3):248; Mathur et al. J Leukoc Biol. 2018, 103:233).   Materials and methods Several series of NLRP3 inhibitory compounds has been synthetized by SynBioMed group of the Department of Drug Science and Technology of Turin through the chemical modulation of a benzo[d]imidazol-1-one sub-moiety, which was identified as a weak inhibitor of ATPase activity. Their protective effect on pyroptosis was evaluated on THP-1 cell lines, after stimulation with LPS/ATP, comparing their activity to that of known inhibitors, such as MCC950 (Coll et al., Nat Med. 2015, 21(3):248); to evaluate this effect, LDH levels was measured using LDH cytotox 96 non radio cytotoxicity assay (Promega). We also evaluated the cytotoxicity of these compounds and the release of Il-1beta. Results Compounds with a N-piperidin acrylamide moiety showed a greater antipyroptotic effect than propanamide derivates; no compounds showed a significant cytotoxicity. Discussion and conclusion Several non-cytotoxic acrylamide and propanamide derivatives able to target the activation of the NLRP3 inflammasome were obtained. Among the acrylamide derivates, we can find promising compounds able to reduce LDH release induced by LPS/ATP. Further studies will be performed in order to better characterize the antipyroptotic activity of these new compounds and to chemically modulate their structure to increase their ability to inhibit NLRP3 inflammasome.     

Pharmacological characterization of new NLRP3 inflammasome inhibitors.

https://iris.unito.it/bitstream/2318/1755487/1/inflammasoma.pdf

Pharmacological characterization of new NLRP3 inflammasome inhibitors.

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