Multi target ligands for promoting inflammation resolution

The resolution of inflammation is a crucial physiological process that limits inflammatory processes, promotes the repair and regeneration of damaged tissue, and facilitates the return to tissue homeostasis. Lipid mediators (LM) are potent autacoids produced from polyunsaturated fatty acids (PUFA) via cyclooxygenase (COX) and lipoxygenase (LOX) pathways, which regulate all stages of inflammation – from initiation, progression, and maintenance to resolution. Smart manipulation of COX/LOX pathways/networks by small molecules that act at multiple enzymes may synergistically accomplish the blockade of inflammation with concurrent promotion of inflammation resolution. We discovered a variety of multiple-target ligands (MTL) that act as LM network modulators (natural products and synthetic small molecules) to block pro-inflammatory but to promote pro-resolving pathways. Thus, these compounds inhibit pro-inflammatory prostaglandin and leukotriene formation but simultaneously stimulate specialized pro-resolving mediator (SPM) production. On the molecular level, these MTL inhibit selected pro-inflammatory enzymes within the 5-LOX/COX pathways but stimulate 12/15-LOX activities which synergistically improves their efficacy versus single-target drugs. Our findings suggest that MTLs could promote the body's own production of pro-resolving LM in order to actively resolve inflammation and restore tissue homeostasis.