Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA.
Bioorg Med Chem Lett. 2011 Nov 15;21(22):6746-50. doi: 10.1016/j.bmcl.2011.09.048. Epub 2011 Sep 20.
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.
白三烯 A(4)水解酶是一种具有双重功能的酶，具有以下两种催化活性：环氧化物水解酶功能，将脂质代谢物白三烯 A(4)转化为白三烯 B(4)；以及氨肽酶功能，水解短肽。迄今为止，所有的药物发现工作都集中在酶的环氧化物水解酶活性上，因为其代谢物白三烯 B(4)的促炎特性已经得到了广泛的生物学表征。在此，我们设计了一种小分子 4-甲氧基二苯甲烷，作为一种具有生物利用度的药理学试剂，可增强白三烯 A(4)水解酶的氨肽酶活性。我们的药物的临床前评估表明，它可以预防鼻内弹性蛋白酶诱导的小鼠模型中的肺肺气肿。
