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4k8s

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Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity

Structural highlights

4k8s is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads 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.^[1] ^[2]

Publication Abstract from PubMed

We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid beta-peptide (Abeta)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.,Pennington LD, Whittington DA, Bartberger MD, Jordan SR, Monenschein H, Nguyen TT, Yang BH, Xue QM, Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, Patel VF, Hitchcock SA, Zhong W Bioorg Med Chem Lett. 2013 Aug 1;23(15):4459-64. doi: 10.1016/j.bmcl.2013.05.028., Epub 2013 May 16. PMID:23769639^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Pennington LD, Whittington DA, Bartberger MD, Jordan SR, Monenschein H, Nguyen TT, Yang BH, Xue QM, Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, Patel VF, Hitchcock SA, Zhong W. Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity. Bioorg Med Chem Lett. 2013 Aug 1;23(15):4459-64. doi: 10.1016/j.bmcl.2013.05.028., Epub 2013 May 16. PMID:23769639 doi:10.1016/j.bmcl.2013.05.028