Enzyme modulators to promote lipid mediator class switching

While cyclooxygenases and 5-lipoxygenase are primarily involved in the formation of pro-inflammatory prostaglandins or leukotrienes, respectively, the two isoforms of 15-lipoxygenase play key roles in the formation of inflammation-resolving lipid mediators. Smart manipulation of the lipoxygenase/cyclooxygenase pathways by small molecules that act on multiple enzymes and redirect substrates (shunting) or regulate the expression of these enzymes in different ways (COX↓, 5-LOX↓, 15-LOX↑) can synergistically block inflammation while simultaneously promoting inflammation resolution. Building on our discoveries of lipid mediator network modulators (glucocorticoids, boswellic acids, cannabidiol, celastrol, etc.), we identify and optimize multi-target ligands that block the formation of prostaglandins and leukotrienes, but at the same time promote the biosynthesis of SPM through lipoxygenase activation. For these projects we use primary human/murine neutrophils, monocytes, platelets and macrophages in both single and co-cultures, and inflammatory in vivo models.

Key publications:

Gilbert N.C., Gerstmeier J., Schexnaydre E.E., Börner F., Garscha U., Neau D.B., Werz O.*, Newcomer M.E.* (2020) Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products. Nat Chem Biol, 16, 783-790

Rao Z, Brunner E, Giszas B, Iyer-Bierhoff A, Gerstmeier J, Börner F, Jordan PM, Pace S, Meyer KPL, Hofstetter RK, Merk D, Paulenz C, Heinzel T, Grunert PC, Stallmach A, Serhan CN, Werner M, Werz O. (2023) Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution. Proc. Natl. Acad. Sci. USA, 120(35):e2302070120

Collaborative Research Centers/Research groups: 

DFG SFB1127 „ChemBioSys“

DFG SFB1278 „Polytarget“

TAB-Forschergruppe “Nature4HEALTH“