Work

Selectively targeting LTA4H aminopeptidase activity for the development of novel anti-inflammatory drugs

Year: 2017

Type: article

Abstract: Leukotriene A 4 hydrolase (LTA4H) plays a critical role in inflammation, the immune response and host defense against infection.This bi-functional enzyme possesses epoxy hydrolase (EH) activity in inflammatory pathways and aminopeptidase (AP) activity in anti-inflammatory pathways.LTA 4 H EH activity catalyzes hydrolysis of leukotriene A 4 (LTA 4 ) to LTB 4 , a proinflammatory lipid mediator that contributes to pulmonary inflammation, irritable bowel syndrome (IBS), COPD, and adult respiratory distress syndrome (ARDS).The LTA 4 H AP activity catalyzes the hydrolysis of the peptide proline-glycine-proline (PGP), a chemotactic peptide resulting from breakdown of collagen.One of the hallmarks associated with inflammatory lung diseases is high concentrations of PGP, which maintains neutrophilic inflammation.Given its role in inflammation, several groups have developed compounds for the non-selective inhibition of LTA 4 H's hydrolytic activity, which resulted in the simultaneous inhibition of both pro-inflammatory and anti-inflammatory pathways.Although the EH and AP functions of LTA 4 H share the same catalytic site, recently, we and others have sought to selectively target each function.We propose a novel therapeutic strategy of selectively augmenting LTA 4 H AP activity with de novo preservation of the EH activity as treatment for inflammatory diseases.We have recently designed and tested a new molecule in two murine in vivo models to demonstrate potentiation of LTA 4 H AP activity as an effective therapeutic approach.This anti-inflammatory compound was evaluated for enhancement of LTA 4 H AP activity in kinetic assays, and the crystal structure of LTA 4 H bound to the compound was determined.The anti-inflammatory compound increased catalytic efficiency and substrate binding 10-fold.For structure determination, LTA 4 H crystal drops were overlaid with the antiinflammatory compound to achieve co-crystals that diffracted to 2.9Å.The structure was determined using molecular replacement and revealed that the anti-inflammatory compound was stabilized by van der Waals interactions and hydrophobic interactions within the aromatic

Source: Acta Crystallographica Section A Foundations and Advances

DOI: 10.1107/s0108767317096209