Macrocyclic peptidomimetic inhibitors of β-secretase (BACE): First X-ray structure of a macrocyclic peptidomimetic-BACE complex

The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 Å resolution. This molecule inhibits the production of the Aβ peptide in HEK293 cells overexpressing APP751sw.

Graphical abstractThe synthesis of novel macrocyclic peptidomimetic inhibitors of BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 Å resolution. This molecule inhibits the production of the Aβ peptide in HEK293 cells overexpressing APP751sw.Figure optionsDownload full-size imageDownload as PowerPoint slide