Al-Awadhi, Fatma, Ratnayake, Ranjala, Paul, Valerie J., and Luesch, Hendrik. 2016. "Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium." Bioorganic & medicinal chemistry 24 (15):3276-3282. https://doi.org/10.1016/j.bmc.2016.04.062
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 57 nM, 23.1 nM, and 0.69 µM, 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 regulation of immune responses, respectively, and these proteases represent potential therapeutic targets.