Planta Med 2015; 81 - PQ5
DOI: 10.1055/s-0035-1556339

Biphasic modulation of human cathepsin L by a novel cyanobacterial depsipeptide

B Miller 1, M Bertin 1, V Hook 2, WH Gerwick 1, 2
  • 1Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA
  • 2Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA

Target-based screening of marine cyanobacterial extracts for small molecule modulators of human cathepsin L, an intriguing target in both cancer and diseases related to the neurosciences, has led to the isolation of a novel depsipeptide natural product. This compound displays an interesting biphasic dose-response against the purified enzyme, characterized by activation at low doses and inhibition at high concentrations. Partial structural determination, based on NMR and MS2 spectroscopy, has identified multiple modified residues, including the hydroxy acid form of methionine sulfoxide, 3-methyl-2-aminopentanoic acid, and N-O-dimethyl tyrosine. A complete structure and kinetic analysis of enzyme modulation will be presented.