| Structural highlights
Function
BACE2_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors.
Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.,Fujimoto K, Matsuoka E, Asada N, Tadano G, Yamamoto T, Nakahara K, Fuchino K, Ito H, Kanegawa N, Moechars D, Gijsen HJM, Kusakabe KI J Med Chem. 2019 May 23;62(10):5080-5095. doi: 10.1021/acs.jmedchem.9b00309. Epub, 2019 May 13. PMID:31021626[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999 Dec 2;402(6761):533-7. PMID:10591213 doi:10.1038/990107
- ↑ Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, Tew DG, Meek TD, Chapman C, Schneider K, Ratcliffe SJ, Tattersall D, Testa TT, Southan C, Ryan DM, Simmons DL, Walsh FS, Dingwall C, Christie G. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci. 2000 Nov;16(5):609-19. PMID:11083922 doi:10.1006/mcne.2000.0884
- ↑ Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J. 2005 May;19(7):739-49. PMID:15857888 doi:10.1096/fj.04-3426com
- ↑ Yan R, Munzner JB, Shuck ME, Bienkowski MJ. BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem. 2001 Sep 7;276(36):34019-27. Epub 2001 Jun 22. PMID:11423558 doi:10.1074/jbc.M105583200
- ↑ Sun X, He G, Song W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. FASEB J. 2006 Jul;20(9):1369-76. PMID:16816112 doi:10.1096/fj.05-5632com
- ↑ Fujimoto K, Matsuoka E, Asada N, Tadano G, Yamamoto T, Nakahara K, Fuchino K, Ito H, Kanegawa N, Moechars D, Gijsen HJM, Kusakabe KI. Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2. J Med Chem. 2019 May 23;62(10):5080-5095. doi: 10.1021/acs.jmedchem.9b00309. Epub, 2019 May 13. PMID:31021626 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00309
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