Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium

Fatma H Al-Awadhi; Ranjala Ratnayake; Valerie J Paul; Hendrik Luesch

doi:10.1016/j.bmc.2016.04.062

Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium

Bioorg Med Chem. 2016 Aug 1;24(15):3276-82. doi: 10.1016/j.bmc.2016.04.062. Epub 2016 Apr 30.

Authors

Fatma H Al-Awadhi¹, Ranjala Ratnayake¹, Valerie J Paul², Hendrik Luesch³

Affiliations

¹ Department of Medicinal Chemistry, University of Florida, Gainesville, USA; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, USA.
² Smithsonian Marine Station, Fort Pierce, FL, USA.
³ 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.

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.

Keywords: Cathepsins D and E; Marine cyanobacteria; Molecular docking; Natural products; Protease inhibitors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cathepsin D / antagonists & inhibitors*
Cathepsin D / chemistry*
Cathepsin E / antagonists & inhibitors*
Cathepsin E / chemistry*
Cyanobacteria / chemistry
Molecular Docking Simulation
Oligopeptides / chemistry*
Oligopeptides / pharmacology*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Seafood / analysis

Substances

Oligopeptides
Protease Inhibitors
tasiamide
Cathepsin E
Cathepsin D

Grants and funding

R01 CA172310/CA/NCI NIH HHS/United States