title: Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium.
abstract: In search of novel protease inhibitors with therapeutic potential, our efforts exploring the marine cyanobacterium Lyngbya sp. have led to the discovery of tasiamide F (1), which is an analogue of tasiamide B (2). The structure was elucidated using a combination of NMR spectroscopy and mass spectrometry. The key structural feature in 1 is the presence of the Phe-derived statine core, which contributes to its aspartic protease inhibitory activity. The antiproteolytic activity of 1 and 2 was evaluated in vitro against cathepsins D and E, and BACE1. Tasiamide F (1) displayed IC50 values of 57nM, 23nM, and 0.69μM, respectively, indicating greater selectivity for cathepsins over BACE1 compared with tasiamide B (2). Molecular docking experiments were carried out for compounds 1 and 2 against cathepsins D and E to rationalize their activity towards these proteases. The dysregulated activities of cathepsins D and E have been implicated in cancer and modulation of immune responses, respectively, and these proteases represent potential therapeutic targets.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, USA; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, USA.
authors.forename: Fatma H
authors.initials: FH
authors.lastname: Al-Awadhi
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, USA; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, USA.
authors.forename: Ranjala
authors.initials: R
authors.lastname: Ratnayake
authors.affiliation: Smithsonian Marine Station, Fort Pierce, FL, USA.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Paul
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, USA; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, USA. Electronic address: luesch@cop.ufl.edu.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020059:Cathepsin E / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000458:Cyanobacteria / Q000737:chemistry; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017747:Seafood / Q000032:analysis
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; C470799:tasiamide; D020059:Cathepsin E; D002402:Cathepsin D
keywords: Cathepsins D and E; Marine cyanobacteria; Molecular docking; Natural products; Protease inhibitors