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

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 angstrom) and BACE2 bound to compound 3 (3.0 angstrom 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.

Automated summary

This study developed a platform to produce large amounts of pure BACE2 protein and designed compounds that selectively inhibit BACE1 over BACE2. The research findings could lead to the quicker development of new selective BACE inhibitors for treating Alzheimer's disease or type II diabetes.