Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities

Abstract

Asperterpenes A (<b>1</b>) and B (<b>2</b>), two 3,5-dimethylorsellinic acid-based meroterpenoids that contain a unique β-oriented Me-21 with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety, were obtained from <i>Aspergillus terreus</i> in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of <b>1</b> was determined using X-ray diffraction. Because of the low yield of <b>1</b>, a comprehensive characterization of the BACE1 inhibitory activities of <b>1</b> was completed <i>via</i> molecular biological, cell and animal studies guided by <i>in silico</i> target confirmation (ISTC). ISTC assays suggested that compounds <b>1</b> and <b>2</b> might be BACE1 inhibitors. In cell-based tests, asperterpenes A and B, as natural products, exhibited promising inhibitory activities against BACE1, with IC₅₀ values of 78 and 59 nM, respectively. LY2811376 (the positive control), one of the most potent clinical BACE1 inhibitors, has shown an IC₅₀ value of 260 nM. <i>In vivo</i>, compound <b>1</b> exhibited activity similar to that of LY2811376 against Alzheimer's disease (AD) in 3xTg AD mice. Taken together, these findings demonstrate that asperterpene A, which contains a novel carbon skeleton, is the first terpenoid to exhibit effective BACE1 inhibitory activity. Moreover, <b>1</b> represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.