Marine Natural Products as Modulators of Human Cathepsin Proteases

While human reliance on the natural environment for medicines has remained relatively constant throughout our history, the places we look and methods we use have changed dramatically. Early civilizations relied on trial-and-error evaluation of terrestrial plants to cure ailments, but today's extensive knowledge about biodiversity, biosyntheitic potential of microorganisms, and access to sensitive analytical chemistry tools has opened up new worlds for the discovery of compounds that can be used as pharmaceutical leads. One of the great leaps for natural products chemistry was the initial exploration of the marine environment, which was untouched in terms of natural products research until the mid-20th century. Still only a small percentage of the diversity of the oceans has been chemically investigated, and the development of new tools is constantly allowing deeper chemical profiling of organisms that were previously thought to be well understood chemically. Marine filamentous cyanobacteria, for example, are prolific producers of structurally complex secondary metabolites with a wide range of bioactivities. While these organisms have been collected, extracted, and assayed for decades, new compounds with exciting activity and therapeutic potential are still regularly being described. Some tried and true methods of natural products research, such as assay-guided isolation, continue to be fruitful in this search. But at a time when so many researchers are investigating natural products from similar environments, novel approaches can be utilized to limit the common complications of natural products chemistry, including lengthy isolation and structure elucidation processes, re-isolation of known compounds, and detection of low abundance metabolites. The work in this dissertation ties together the old methods and the new, including a traditional screening campaign that resulted in an assay-guided isolation of a known compound with a new activity, as well as a high-throughput screening campaign integrated with high resolution metabolomic data for rapid identification of novel compounds. Both screening campaigns were successful in providing novel insights in the realm of cyanobacterial natural products from the marine environment, each with their own challenges and advantages