Discovery of an Indole-Quinazoline Alkaloid as an Anti-kidney Fibrotic Agent from the Marine-Derived Aspergillus clavatonanicus SCSIO 41444.

Kidney fibrosis represents a hallmark pathological outcome in the progression of chronic kidney diseases. The clinical approval of therapeutics specifically for kidney fibrosis remains lacking to date. Toward the discovery of novel marine-derived drugs leads against kidney fibrosis, a fibronectin (FN)-based assay was used to screen various fractions of the crude extract from the growth medium of sponge-associated fungus Aspergillus clavatonanicus SCSIO 41444. A bioassay-guided fractionation process yielded six active compounds (1-6), including a new indole-quinazoline alkaloid (1) and an undescribed pyripyropene-type alkaloid (2). The structures and absolute configurations of 1 and 2 were determined by analysis of spectroscopic data and electron circular dichroism calculations. Compounds 1-6 (10 μM) were all active in the TGF-β1-stimulated HK-2 cell model of kidney fibrosis. The alkaloid 1 demonstrated potent activity, significantly suppressing the protein levels of FN and α-SMA at a concentration as low as 2.5 μM. Based on comprehensive proteomic analysis, 1 was found to decrease thyroid adenoma-associated protein levels, thereby modulating endoplasmic reticulum calcium homeostasis and influencing the progression of kidney fibrosis. These findings suggested that 1 is a promising anti-kidney fibrosis agent with a new mechanism for drug development.