title: Efficient inhibition of human leukocytic elastase by means of α1-antitrypsin/peptide complexes.
abstract: α1 -Antitrypsin (AT), a serine protease inhibitor that specifically targets hydrolytic enzymes, plays a significant role in the termination of tissue inflammation and can therefore represent a key factor in chronic incidences as chronic obstructive pulmonary disease (COPD) or chronic hepatitis. A local and low-dose therapy for the treatment of acquired chronic inflammatory processes which are characterized by insufficient AT amounts but also of genetically conditioned AT deficiencies is supposed to be more effective and less cost-intensive compared to current therapies. In this study, a noncovalent complex formation between the cell-penetrating peptide carrier hCT(18-32)-k7 and AT was performed. The complex was applied to HEK293T/17 cells, as proof-of-principle, and polymorphonuclear leukocytes (PMN), which are responsible for tissue destruction and the perpetuation of inflammation in chronic processes. Both cell species show a successful uptake and subsequently both, an intracellular dot-shaped and homogeneous distribution of the complex demonstrating phagolysosomal as well as cytoplasmic availability. Furthermore, a decreased human leukocytic elastase (HLE) activity was observed after the direct complex administration to PMN. Since the application did not cause an enhanced vitality loss, the complex could facilitate an improvement in direct, local and low-dose treatment of chronically proceeding processes in order to attenuate protease-mediated tissue destruction.
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore. jacquelineelenalessig@gmail.com
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Leßig
authors.forename: Uta
authors.initials: U
authors.lastname: Reibetanz
authors.forename: Maria
authors.initials: M
authors.lastname: Schönberg
authors.forename: Ines
authors.initials: I
authors.lastname: Neundorf
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D057809:HEK293 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000494:pharmacology* / Q000627:therapeutic use; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000515:alpha 1-Antitrypsin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D057846:Cell-Penetrating Peptides; D009097:Multienzyme Complexes; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase