Emphysematous chronic obstructive pulmonary disease (COPD) is an irreversible lung disease of increasing prevalence for which effective disease modifying therapy is not available. Patients with COPD exhibit dysregulated and exaggerated inflammatory and immunologic responses. Recent studies have shown that the aminopeptidase activity of the leukotriene A4 hydrolase (LTA4H) enzyme may play crucial roles in the process of resolving inflammation. We have independently demonstrated effective protection of murine lungs against COPD by selectively augmenting the LTA4H aminopeptidase activity with 4MDM, a selective small molecule activator of the LTA4H aminopeptidase activity. When COPD was induced with cigarette smoke, treatment with 4MDM significantly reduced severity of COPD as determined by pre-mortem physiologic and post-mortem anatomic assessment. On the basis of these findings, we believe that 4MDM can serve as a lead molecule for the discovery of novel anti-inflammatory agents to treat COPD. Therefore, we propose specific aims to better understand the target LTA4H enzyme structure, discover new activators of the LTA4H aminopeptidase activity, and determine the effect of these compounds in the pathogenesis of COPD. We believe that our proposed work and expected outcomes will provide potential first-in-class drugs to treat patients with COPD.

Public Health Relevance

Emphysematous chronic obstructive pulmonary disease (COPD) is an irreversible lung disease of increasing prevalence for which effective disease modifying therapy is not available. Based on these needs, we propose specific aims to design and synthesize new compounds that activate the LTA4H aminopeptidase activity as a target for treating COPD. We believe that our proposed work and expected outcomes will lead to new understandings of the conventional knowledge and therapeutic options associated with the biology of LTA4H enzyme and COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132287-02
Application #
9282798
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Punturieri, Antonello
Project Start
2016-06-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$606,053
Indirect Cost
$51,377
Name
George Mason University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077817450
City
Fairfax
State
VA
Country
United States
Zip Code
22030
Han, Claudia Z; Juncadella, Ignacio J; Kinchen, Jason M et al. (2016) Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539:570-574