title: Harnessing the natural inhibitory domain to control TNFα Converting Enzyme (TACE) activity in vivo.
abstract: Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto-inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell-surface TACE, but not the related ADAM10, and effectively modulated TNFα secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFα in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eitan
authors.initials: E
authors.lastname: Wong
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Cohen
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Romi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Maxim
authors.initials: M
authors.lastname: Levin
authors.affiliation: The Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Peleg
authors.affiliation: Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Arad
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Yaron
authors.affiliation: Janssen Research &Development, San Diego, CA, USA.
authors.forename: Marcos E
authors.initials: ME
authors.lastname: Milla
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000072198:ADAM17 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003094:Collagen / Q000009:adverse effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000072417:Protein Domains; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014302:Trinitrobenzenesulfonic Acid; D003094:Collagen; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein