Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system

Abstract

Abstract15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.

Leishmania infantum-exploited Nrf2 transcription factor as a virulence process to escape macrophage-driven ferroptosis-like leishmanicidal process

“…In the delayed phases of L. infantum infection, pharmacological inhibition of PGE2 synthase and the EP2 receptor drastically reduced Nrf2 nuclear translocation in murine and human macrophages, strengthening COX-2/PGEs/PGE2/EP2r axis in the maintaining Nrf2 activation. The increase in parasite load in mice treated with the inhibitor of 15-PGDH, a prostaglandin-degrading enzyme (Huang et al , 2023), reinforces the importance of this signaling pathway and the crucial contribution of PGE2 via EP2r and not its metabolites in the progression of infection. Collectively, our data show the contribution of NOX2/ROS axis in the early activation of Nrf2 and the subsequent involvement of PGE2/EP2r in the sustainment of this activation upon L. infantum infection.…”