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

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.

SUBMITTER: Yen YC

PROVIDER: S-EPMC9535992 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Yen Yu-Chen YC Kammeyer Annalissa M AM Tirlangi Jagannadharao J Ghosh Arun K AK Mesecar Andrew D AD

ACS chemical neuroscience 20210205 4

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 <i>E. coli</i> culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound <b>2</b> was found to potently inhibit BAC ...[more]

PMID: 33544569

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