Natural Product Mining of Archived Corals

Project Summary
Natural products have a long history of use in modern medicine but have recently declined as a proportion of New
Chemical Entities advancing to clinical use. Among the serious challenges of natural product discovery studies is
the re-isolation of known and well-studied chemotypes, despite the fact that the vast majority of biodiversity has
not been subject to chemical analyses. Less than 20% of octocoral species, for example, have natural products
reported in MarinLit, the foremost database of marine chemistry. After sponges, octocorals are the primary source
of bioactive and structurally unique marine natural products. One reason for the disparity in chemical analysis of
octocorals is that many unstudied or understudied specimens are difficult to access, inhabiting environments such
as the deep sea, polar waters or in geopolitically problematic regions. To address the limited access to
underrepresented marine organisms, we propose to study the marine invertebrate holdings of natural history
museums (NHM’s). With recent advances in analytical instrumentation and analysis platforms, it is increasingly
possible to characterize low levels of metabolites. Orbitrap and QToF mass spectrometers, coupled with nanoflow
liquid chromatographs, are capable of separation and highly accurate mass measurements of even trace
metabolites in complex mixtures. Bioinformatic platforms such as MZmine are adept at deconvoluting mass data
to identify individual features (~molecules and their fragmentation products), which can then be parsed by e.g.
SIRIUS, which uses machine learning and database comparisons to interpret those features and predict structural
fragments or even de novo putative structural assignments. Validation of putative structures from mass data can
be achieved even in mixtures with targeted NMR sequences such as PSYCHE-TOCSY and DREAMTIME.
Further, computational approaches such as Density Functional Theory (DFT) provide chemical shift predictions
that can be used to propose stereochemical assignments. These advances open the door to vigorous analysis of
samples archived in NHM’s, samples that span both geographic and temporal space that is often inaccessible to
chemist-collectors. Not only do NHM’s provide diverse samples, but the samples are identified by experts in their
field and they are geotagged and fully permitted. The Smithsonian Institution’s National Museum of Natural
History (NMNH) maintains a warehouse with decades to more than a century of collections of ethanol-preserved
marine invertebrates. Sampling the ethanol from several coral species in the NMNH, our preliminary analysis
demonstrates the potential of these samples to yield new natural products. This project seeks to validate the
NMNH samples as a significant drug discovery resource by identifying new metabolites in one well known coral
species as well as characterization of new chemotypes from one or more previously unstudied coral species.

Grant Number: 1R21AT012954-01A1
NIH Institute/Center: NIH
Principal Investigator: BILL BAKER