Issue 10, 2016

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

Abstract

Asperterpenes A (1) and B (2), 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 Aspergillus terreus in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of 1 was determined using X-ray diffraction. Because of the low yield of 1, a comprehensive characterization of the BACE1 inhibitory activities of 1 was completed via molecular biological, cell and animal studies guided by in silico target confirmation (ISTC). ISTC assays suggested that compounds 1 and 2 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. In vivo, compound 1 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, 1 represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
04 Jun 2016
Accepted
25 Jun 2016
First published
27 Jun 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 6563-6572

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

C. Qi, J. Bao, J. Wang, H. Zhu, Y. Xue, X. Wang, H. Li, W. Sun, W. Gao, Y. Lai, J. Chen and Y. Zhang, Chem. Sci., 2016, 7, 6563 DOI: 10.1039/C6SC02464E

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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