Sulphonylureas as Adjunct Therapeutic Agents in the Treatment of Autoimmune Conditions: A Narrative Review

Abstract

A rapid and cost-effective arm of the drug discovery and development process is finding new uses for existing drugs. Initially used as antibacterial agents, sulphonylureas were repurposed for the treatment of type 2 diabetes due to their hypoglycemic side effects. Their primary mechanism of action is mediated by binding to sulphonylurea receptors (SUR), which are atypical adenosine triphosphate binding cassette transporters in pancreatic beta cells. This interaction inhibits ATP-sensitive potassium channels to promote insulin release. Off-target actions of sulphonylureas identified in recent studies have demonstrated a range of anti-inflammatory properties mediated by modulation of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 inflammasomes. Inflammasomes are cytosolic protein complexes that assemble in response to infection or stress-associated stimuli, activating inflammatory responses, and are the primary source of pro-inflammatory cytokines. Sulphonylureas and their derivatives have been shown to inhibit various stages of inflammasome activation, leading to the reduction of pro-inflammatory mediators, including IL-1β and IL-18. Recent evidence demonstrates that these agents reduced inflammatory responses, disease severity, and progression in various preclinical autoimmune and inflammatory models. In this narrative review, we consider the complexity of autoimmune conditions and the limited treatment options, and highlight the potential value of repurposing sulphonylureas and their derivatives as adjunct therapeutics for autoimmune conditions.

FIGURE 1

Signaling cascade and regulation points of the NLRP3 inflammasome. Inflammasome upregulation in monocytes, macrophages, and neutrophils occurs when TLR4 receptors are activated (1) causing translocation of NF‐κB (2), increasing production of the NLRP3 sensor, pro‐IL‐1β and pro‐IL‐18 (3). The second signal caused by DAMPs, ROS, and low intracellular potassium (K⁺) (4) activates the NLRP3 sensor, triggering recruitment and oligomerisation (5). Auto‐cleavage of the pro‐caspase‐1 region (6) results in its activation and the subsequent activation of IL‐1β, IL‐18, and the pore‐forming GSDMD (7). ASC, apoptosis‐associated speck‐like protein containing a caspase recruitment domain; DAMPs, danger associated molecular pattern; GSDMD, gasdermin D; IKKβ, inhibitor of nuclear factor kappa B kinase subunit β; IL, interleukin; LRR, leucine‐rich repeat; NACHT, central nucleotide‐binding domain; NF‐κB, nuclear factor kappa B; NLRP3, nucleotide‐binding domain, leucine‐rich–containing family, pyrin domain–containing‐3; P2X7, P2X purinoceptor 7; PYD, pyrin domain; ROS, reactive oxygen species; TLR4, toll‐like receptor‐4. Adapted from [9, 17, 18] (Created with biorender.com).

FIGURE 2

IL‐1β signaling cascade. In monocytes, macrophages, and B and T cells, activation of IL‐1R (1) by IL‐1β results in translocation of the transcription factors NF‐κB and CREB (2), which are responsible for the upregulation of multiple effector molecules associated with several autoimmune conditions (3). COX‐2, cyclooxygenase 2; CREB, cAMP‐response element binding protein; IKKβ, inhibitor of nuclear factor kappa B kinase subunit β; IL, interleukin; iNOS2, inducible nitric oxide 2; MAPK3, mitogen‐activated protein kinase 3; MEKK3/6, mitogen‐activated protein/ERK kinase kinase 3/6; NF‐κB, nuclear factor kappa B; p38, protein 38; TNF‐α, tumor necrosis factor‐alpha. Adapted from [41, 42] (Created with biorender.com).