Kinase signaling as a drug target modality for regulation of vascular hyperpermeability: A case for ARDS therapy development

Abstract

The endothelial vascular permeability barrier has an important role throughout the body's extensive vasculature, and its disruption leads to vascular hyperpermeability (leakage), which is associated with numerous medical conditions. In the lung, vascular hyperpermeability can lead to pulmonary edema and acute respiratory distress syndrome (ARDS), the most severe and deadly complication of viral and bacterial infections, trauma and radiation exposure. There is currently no pharmacological treatment for ARDS with the only approved options being focused on supportive care. The development of effective treatments for ARDS has a potential to turn infectious diseases such as bacterial and viral pneumonia (including COVID-19) into manageable conditions, saving lives and providing a new tool to combat future epidemics. Strategies that aim to protect and augment the vascular endothelial barrier are important avenues to consider as potential treatments for ARDS and other conditions underlined by vascular hyperpermeability. We propose the activation of the MAPKAPK2 (MK2) kinase pathway as a new approach to augment the endothelial barrier and prevent or reverse ARDS and other conditions characterized by vascular barrier dysfunction.

Keywords: ARDS; Drug discovery; Druggable pocket; MK2 pathway; Vascular leak.