From Toxic Gas to Treatment Tool: Development of a Sulfide-Based Prototype Drug for IDO1 and Identifying Novel Residues of Interest for Catalytic Function

Abstract

Immune checkpoint enzyme indoleamine 2,3-dioxygenase (IDO1) is an important target for both cancer and auto-immune disease therapies. Here it is shown that IDO1 is activated by both hydrogen sulfide and polysulfides, potentially revealing a new cellular signaling pathway and inspiring a catalytic agonist with similar properties, 3-mercaptoindole (3MI). Polysulfides and 3MI reduce the inactive ferric heme cofactor of IDO1 to the active ferrous form, sustaining turnover. 3MI exhibits rapid inhibition, likely from the off-target reduction of the active ferric superoxo complex, but tolerates chemical group substitutions without loss of its activation properties. Preliminary gaussian modelling of 3MI analogues suggests its utility for identifying analogues of interest. Bioinformatic analysis of the IDO1 gene and the reimagining of IDO1 as evolutionary-linked protein sectors suggest novel residues to target with mutational studies to better understand the key structural and catalytic components of the enzyme.