Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema |
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| Authors: | De Oliveira Eliseu O Wang Kan Kong Hye-Sik Kim Suhyon Miessau Matthew Snelgrove Robert J Shim Y Michael Paige Mikell |
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| Affiliation: | Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA. |
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| Abstract: | The leukotriene A(4) hydrolase enzyme is a dual functioning enzyme with the following two catalytic activities: an epoxide hydrolase function that transforms the lipid metabolite leukotriene A(4) to leukotriene B(4) and an aminopeptidase function that hydrolyzes short peptides. To date, all drug discovery efforts have focused on the epoxide hydrolase activity of the enzyme, because of extensive biological characterization of the pro-inflammatory properties of its metabolite, leukotriene B(4). Herein, we have designed a small molecule, 4-methoxydiphenylmethane, as a pharmacological agent that is bioavailable and augments the aminopeptidase activity of the leukotriene A(4) hydrolase enzyme. Pre-clinical evaluation of our drug showed protection against intranasal elastase-induced pulmonary emphysema in murine models. |
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| Keywords: | 4-MDM, 4-methoxydiphenylmethane AC50, concentration at 50% enzyme augmentation Ala-p-NA, smallcaps" >l-alanine p-nitroanilide COPD, chronic obstructive pulmonary disease IN, Intranasal IP, intraperitoneal LTA4, leukotriene A4 LTA4H, leukotriene A4 hydrolase LTB4, leukotriene B4 PGP, proline-glycine-proline WT, wild-type |
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