Chronic obstructive lung diseases (COLD), such as asthma and COPD are major health issues, especially in modernized countries, and for which there are currently no curative therapies. Respiratory viral infections have been implicated in both development and exacerbation of COLD. Utilizing a mouse model of paramyxoviral infection, we have shown that infection with Sendai virus (SeV) leads to a long-lasting post-viral COLD with airway hyperreactivity and mucous cell metaplasia. This post-viral disease is dependent upon production of the chemokine CCL28 from lung dendritic cells. CCL28 has two ligands, CCR3 and CCR10, although it is not known through which of these receptors it exerts its effects in the SeV model. Antagonizing the effect of CCL28 in this model would be expected to prevent the development of the post-viral disease. We have recently developed a structure-based strategy to identify specific small molecule chemokine inhibitors, based on sulfotyrosine recognition pocket binding, that work by preventing receptor activation by the specific chemokine. We hypothesize that lung-specific CCL28 production is critical to the development of post-viral asthma, and that this process can be inhibited by targeted antagonism of CCL28's function. To test this hypothesis, we propose three specific aims: 1) Test the hypothesis that the CCR10 agonist activity of CCL28 leads to airway hyperresponsiveness and mucous cell metaplasia in a mouse model of obstructive lung disease. 2) Solve the 3D structure of CCL28 and identify important receptor recognition sites by NMR and mutagenesis. 3) Identify small molecule ligands that inhibit CCL28 activity in vitro and test their ability to prevent post-viral asthma in vivo. Upon completion of this project, we will have identified the chemokine receptor through which CCL28 mediates its action in the SeV model. Further, we will have developed at least one small molecule ligand, which antagonizes CCL28 activity in both in vitro and in vivo assays. In the future, these lead compounds could be further studied for potential use as a means to treat and/or prevent chronic obstructive lung disease in humans.
Asthma and chronic obstructive pulmonary disease (COPD) form the spectrum of COLD for which there are no available curative therapies. The risk of developing asthma is greatly increased if the person has had a severe viral respiratory infection. However, we found that blocking the action of a specific inflammatory protein called CCL28 can prevent the symptoms of viral-induced COLD. We propose to search for CCL28 inhibitors using an innovative drug discovery strategy that we devised to target proteins in this family. The development of a novel anti-inflammatory therapy will advance our understanding of airway diseases and address an unmet need for diagnosis and treatment of a public health problem.
| Thomas, Monica A; Buelow, Becky J; Nevins, Amanda M et al. (2015) Structure-function analysis of CCL28 in the development of post-viral asthma. J Biol Chem 290:4528-36 |
