Work

A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors

Year: 2021

Type: article

Abstract: The ability to perform routine structure-guided drug design for selective BACE inhibitors has been limited because of the lack of robust platform for BACE2 expression, purification, and crystallization. To overcome this limitation, we developed a platform that produces 2–3 mg of pure BACE2 protein per liter of E. coli culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound 2 was found to potently inhibit BACE 1 ( K i = 5 nM) with a selectivity of 214-fold over BACE2. The X-ray crystal structures of unbound BACE2 (2.2 Å) and BACE2 bound to compound 3 (3.0 Å and K i = 7 nM) were determined and compared to the X-ray structures of BACE1 revealing the S1–S3 subsite as a selectivity determinant. This platform should enable a more rapid development of new and selective BACE inhibitors for the treatment of Alzheimer’s disease or type II diabetes.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.0c00629

Authors: Yu-Chen Yen, Annalissa M. Kammeyer, Jagannadharao Tirlangi, Arun K. Ghosh, Andrew D. Mesecar

Institution: Purdue University West Lafayette

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institute on Aging, National Cancer Institute