Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol.

Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spid A, 1) with low natural abundance. Remarkably, Spid A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spid A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spid A for treating cardiovascular disease.

Chaetolactam A, an Azaphilone Derivative from the Endophytic Fungus Chaetomium sp. g1.

Chaetolactam A (1), an unprecedented azaphilone derivative bearing a unique 9-oxa-7-azabicyclo[4.2.1]octan-8-onering system, together with two new compounds, 11-epi-chaetomugilide B (2) and chaetomugilide D (3) was isolated from an endophytic fungus, Chaetomium sp. g1. Notably, extensive NMR data analyses, NMR calculations with DP4 and DP4+ analyses, ECD calculations, and the RDC method were employed to establish the structure of 1. Furthermore, 2 exhibited potent apoptosis induction activity by mediating caspase-3 activation and PARP degradation at 3 µM in HL-60.

Discovery of ent-kaurane diterpenoids, characteristic metabolites of Isodon species, from an endophytic fungal strain Geopyxis sp. XY93 inhabiting Isodon parvifolia.

Isogeopyxins A-C (1-3), three new diterpenoids with ent-kaurane, ent-pimarane, and ent-abietane scaffolds, respectively, along with six known ent-kauranoids, were isolated from the fermentation culture of Geopyxis sp. XY93 inhabiting the leaves of Isodon parvifolia. Their structures were elucidated by interpretation of spectroscopic data, and single crystal X-ray diffraction. It marks the first time that ent-kauranoids, characteristic metabolites of Isodon species, have been isolated from an associated endophytic fungus.

Arthrinins E-G, Three Botryane Sesquiterpenoids from the Plant Endophytic Fungus Arthrinium sp. HS66.

Arthrinins E-G (1-3), three new sesquiterpenoids possessing non-isoprenoid botryane skeleton, were isolated from the fermentation of an endophytic fungus named Arthrinium sp. HS66 which colonized in the stems of Isodon xerophilus. Their structures were determined by extensive spectroscopic methods. Furthermore, the structure of 1 was unambiguously confirmed by X-ray diffraction, while those of 2 and 3 were verified through quantum chemical calculation of NMR data and ECD spectra.