IRG1 Inhibitors

The chemical class of IRG1 inhibitors encompasses compounds that can modulate the activity of IRG1, either by direct interaction with the enzyme or by altering the metabolic pathway in which IRG1 is involved. Since there are no known direct inhibitors of IRG1, the chemicals listed above represent indirect approaches to influence IRG1 activity. These approaches are predicated on the understanding that IRG1's enzymatic function is closely tied to the tricarboxylic acid (TCA) cycle and the cellular redox state.

Chemicals such as succinyl-CoA, fluoroacetate, and dimethyl malonate can indirectly inhibit IRG1 by affecting the concentrations of intermediates in the TCA cycle, which is upstream of IRG1's activity in producing itaconate. For instance, fluoroacetate's inhibition of aconitase leads to citrate accumulation, which can reduce the availability of cis-aconitate, the substrate for IRG1. Similarly, dimethyl malonate can impede the functioning of succinate dehydrogenase, potentially affecting the levels of succinate and, subsequently, the availability of substrates for IRG1. Monomethyl fumarate and oxaloacetate can also influence the TCA cycle, thereby altering the metabolic environment in which IRG1 operates. On the other hand, chemicals like gossypol and disulfiram, which inhibit ALDH, can alter the redox balance of the cell, which is known to influence various metabolic pathways including those involving IRG1. N-Ethylmaleimide and arsenite interact with protein thiols, which can affect the activity of enzymes that rely on thiol groups for their catalytic mechanisms. This method of inhibition is more indirect and depends on the structural makeup of IRG1 and the presence of reactive cysteine residues.