title: Prodrug-inspired probes selective to cathepsin B over other cysteine cathepsins.
abstract: Cathepsin B (CTB) is a cysteine protease believed to be an important therapeutic target or biomarker for several diseases including aggressive cancer, arthritis, and parasitic infections. The development of probes capable of assessing CTB activity in cell lysates, living cells, and animal models of disease are needed to understand its role in disease progression. However, discovering probes selective to cathepsin B over other cysteine cathepsins is a significant challenge due to overlap of preferred substrates and binding site homology in this family of proteases. Herein we report the synthesis and detailed evaluation of two prodrug-inspired fluorogenic peptides designed to be efficient and selective substrate-based probes for CTB. Through cell lysate and cell assays, a promising lead candidate was identified that is efficiently processed and has high specificity for CTB over other cysteine cathepsins. This work represents a key step toward the design of rapid release prodrugs or substrate-based molecular imaging probes specific to CTB.
authors.affiliation: Thunder Bay Regional Research Institute, 2321-290 Munro Street, Thunder Bay, Ontario, Canada , P7A 7T1.
authors.forename: Morshed A
authors.initials: MA
authors.lastname: Chowdhury
authors.forename: Ignace A
authors.initials: IA
authors.lastname: Moya
authors.forename: Shardul
authors.initials: S
authors.lastname: Bhilocha
authors.forename: Cody C
authors.initials: CC
authors.lastname: McMillan
authors.forename: Brady G
authors.initials: BG
authors.lastname: Vigliarolo
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Zehbe
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Phenix
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D010455:Peptides; D011355:Prodrugs; C533912:CTSB protein, human; D002401:Cathepsin B