Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 23, Pages 10605-10616Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00663
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Funding
- NIH [R01HL132287]
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Activation of the leukotriene A(4) hydrolase (LTA(4)H) aminopeptidase (AP) activity with 4-methoxydiphenylmethane (4MDM) promoted resolution of neutrophil infiltration in a murine cigarette smoke-induced model for emphysematous chronic obstructive pulmonary disease. Recently, 4-(4-benzylphenyl)-thiazol-2-amine (ARM1) was published as a ligand for LTA(4)H with potential anti-inflammatory properties. To investigate the effect of modifier structure on enzyme kinetics of LTA(4)H, a series of analogues bearing structural features of ARM' and 4MDM were synthesized using trifluoroborate Suzuki coupling reactions. Following, the 2.8 angstrom X-ray crystal structure of LTA(4)H complexed with 4-OMe-ARM1, a 4MDM-ARM1 hybrid molecule, was determined. Kinetic analysis showed that ARM1 and related analogues lowered affinity for the enzyme-substrate complex, resulting in a change of mechanism from hyperbolic mixed predominately catalytic activation (HMx(Sp < Ca)A) as observed for 4MDM to a predominately specific activation (HMx(Sp > Ca)A) mechanism. 4-OMe-ARM1 was then shown to dose responsively reduce LTB4 production in human neutrophils.
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