Exploring Structure Activity Relationships for the Pharmacological inhibition of TWIK-2

Abstract

Sepsis is a complex clinical syndrome which is acknowledged by the WHO as a major global health threat. Sepsis is caused from a dysregulated and excessive inflammatory immune response to tissue damage or infection. Inflammasomes, a set of large multiprotein complexes, play a crucial role as signalling platforms that detect harmful injury mediators and induce an inflammatory response. The NLRP3 (nucleotide-binding oligomerization domain, leucine rich repeat containing proteins) inflammasome is part of the NLR family which acts as pattern-recognition receptors to activate the innate immune system in response to such harmful stimuli. The dysregulated activation of this inflammasome is linked to various auto-inflammatory or chronic inflammations. The biological pathway for the activation of NLRP3 involves a potassium ion efflux which is predominantly produced by a K2P potassium channel TWIK-2. Hence, TWIK-2 acts as a checkpoint for inflammatory signaling mediated by NLRP3. This makes TWIK-2 a potential therapeutic target to suppress NLRP3 based inflammation. Development of inhibitors to block the TWIK-2 K+ channel is currently at an early stage. Recently, a bis-amide ML365, which inhibits TASK-1, was found to inhibit TWIK-2 at an IC50 value of about 10μM. This inhibitor can further be optimized by Structure-Activity Relationships (SAR) to effectively block the potassium channel selectively. In this study, the design, synthesis and characterization of inhibitors inspired from the ML365 scaffold has been achieved to optimize the efficacy and selectivity of blocking the TWIK-2 K+ channel, ultimately regulating inflammatory response by the NLRP3 inflammasome.