Discovery of an Indole-Quinazoline Alkaloid as an Anti-kidney Fibrotic Agent from the Marine-Derived <i>Aspergillus clavatonanicus</i> 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 <i>Aspergillus clavatonanicus</i> SCSIO 41444. A bioassay-guided fractionation process yielded six active compounds (<b>1</b>-<b>6</b>), including a new indole-quinazoline alkaloid (<b>1</b>) and an undescribed pyripyropene-type alkaloid (<b>2</b>). The structures and absolute configurations of <b>1</b> and <b>2</b> were determined by analysis of spectroscopic data and electron circular dichroism calculations. Compounds <b>1</b>-<b>6</b> (10 μM) were all active in the TGF-β1-stimulated HK-2 cell model of kidney fibrosis. The alkaloid <b>1</b> 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, <b>1</b> 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 <b>1</b> is a promising anti-kidney fibrosis agent with a new mechanism for drug development.