Using functional signature ontology (FUSION) to identify mechanisms of action for natural products.

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells.

Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis.

Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5-dione core.

DDR2 plays a role in fibroblast migration independent of adhesion ligand and collagen activated DDR2 tyrosine kinase.

Discoidin domain receptor-2 (DDR2) is a cell surface tyrosine kinase receptor that can be activated by soluble collagen and has been implicated in diverse physiological functions including organism growth and wound repair. In the current studies, we used fibronectin and collagen-coated 2D surfaces and collagen matrices in combination with siRNA technology to investigate the role of DDR2 in a range of fibroblast motile activities. Silencing DDR2 with siRNA inhibited cell spreading and migration, and similar inhibition occurred regardless whether cells were interacting with fibronectin or collagen surfaces.

RFamide neuropeptides inhibit murine and human adipose differentiation.

RFamide neuropeptides NPFF and NPAF affect gene expression in mature 3T3-L1 adipocytes but their role on adipogenesis is unknown. Here, we show that NPFF, NPAF, and NPSF inhibited the differentiation of 3T3-F442A preadipocytes in a concentration-dependent manner, but had no effect on 3T3-L1 adipogenesis. All three neuropeptides also blocked the adipose differentiation of normal and lipoma-derived human preadipocytes.