Biomolecular interactions between the antibacterial ceftolozane and the human inflammatory disease target ADAM17: a drug repurposing study.

Inhibition of a disintegrin and metalloproteinase-17 (ADAM17), a metzincin, is proposed as a novel therapeutic strategy to suppress overproduction of the proinflammatory cytokine TNF-α in rheumatoid arthritis and inflammatory bowel disease. Existing ADAM17 inhibitors generate toxic metabolites in-vivo or haven't progressed in clinical trials. Previous studies suggest that ligands which bind to ADAM17 active site by interacting with the Zn ion and L-shaped hydrophobic S1'- and S3'-pockets and forming favorable hydrogen bonds could act as potential ADAM17 inhibitors. Here, we investigated whether the FDA-approved anti-bacterial drug ceftolozane, a cephalosporin containing aromatic groups and carboxyl groups as probable zinc binding groups (ZBGs), forms non-covalent interactions resulting in its binding in the active site of ADAM17. In this study, the density functional theory (DFT), molecular docking and molecular dynamics calculations with the catalytic chain of ADAM17 show that carboxyl group of ceftolozane acts as moderate ZBG, and its extended geometry forms hydrogen bonds and hydrophobic interactions resulting in a binding affinity comparable to the co-crystallized known ADAM17 inhibitor. The favorable binding interactions identified here suggest the potential of ceftolozane to modulate ADAM17 activity in inflammatory diseases. ADAM17 cleaves and releases epidermal growth factor (EGF) ligands from the cell surface. The shed EGF ligands then bind to the EGF receptors to drive embryonic development. Therefore, our findings also suggest that use of ceftolozane during pregnancy may inhibit ADAM17-mediated shedding of EGF and thus increase the risk of birth defects in humans.Communicated by Ramaswamy H. Sarma.

Novel regulators of airway epithelial barrier function during inflammation: potential targets for drug repurposing.

INTRODUCTION: Endogenous inflammatory signaling molecules resulting from deregulated immune responses can impair airway epithelial barrier function and predispose individuals with airway inflammatory diseases to exacerbations and lung infections. Therapeutically targeting the specific endogenous factors disrupting the airway barrier therefore has the potential to prevent disease exacerbations without affecting the protective immune responses. AREAS COVERED: Here, we review the endogenous factors and specific mechanisms disrupting airway epithelial barrier during inflammation and reflect on whether these factors can be specifically targeted by repurposing the existing drugs. Literature search was conducted using PubMed, drug database of US FDA and European Medicines Agency until and including September 2021. EXPERT OPINION: IL-4 and IL-13 signaling are the major pathways disrupting the airway epithelial barrier during airway inflammation. However, blocking IL-4/IL-13 signaling may adversely affect protective immune responses and increase susceptibility of host to infections. An alternate approach to modulate airway epithelial barrier function involves therapeutically targeting specific downstream component of IL-4/IL-13 signaling or different inflammatory mediators responsible for regulation of airway epithelial barrier. Airway epithelium-targeted therapy using inhibitors of HDAC, HSP90, MIF, mTOR, IL-17A and VEGF may be a potential strategy to prevent airway epithelial barrier dysfunction in airway inflammatory diseases.