PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of neurotherwww.springer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
Neurotherapeutics. 2008 July; 5(3): 399–408.
PMCID: PMC2963069
NIHMSID: NIHMS239580

β-Secretase as a therapeutic target for Alzheimer’s disease

Summary

β-Secretase (memapsin 2, BACE1) is an attractive target for the development of inhibitor drugs to treat Alzheimer’s disease (AD). Not only does this protease function at the first step in the pathway leading to the production of amyloid-β (Aβ), its gene deletion produces only mild phenotypes. In addition, β-secretase is an aspartic protease whose mechanism and inhibition are well known. The development of β-secretase inhibitors, actively pursued over the last seven years, has been slow, due to the difficulty in combining the required properties in a single inhibitor molecule. Steady progress in this field, however, has brought about inhibitors that contain many targeted characteristics. In this review, we describe the strategy of structure-based inhibitor evolution in the development of β-secretase inhibitor drug. The current status of the field offers grounds for some optimism, in that β-secretase inhibitors have been shown to reduce brain Aβ and to rescue the cognitive decline in transgenic AD mice, and an orally available β-secretase inhibitor drug candidate is in clinical trial. With this knowledge base, it seems reasonable to expect that more drug candidates will be tested in human, and then successful disease-modifying drugs may ultimately emerge from this target.

Key Words: β-secretase, amyloid precursor protein secretase, inhibitor drug, Alzheimer’s disease

References

1. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature. 1999;399(6738 Suppl):A23–31. [PubMed]
2. Vassar R, Bennett BD, Babu-Khan S, et al. β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–741. doi: 10.1126/science.286.5440.735. [PubMed] [Cross Ref]
3. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000;97:1456–1460. doi: 10.1073/pnas.97.4.1456. [PubMed] [Cross Ref]
4. Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature. 1999;402:533–537. doi: 10.1038/990107. [PubMed] [Cross Ref]
5. Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature. 1999;402:537–540. doi: 10.1038/990114. [PubMed] [Cross Ref]
6. Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci. 1999;14:419–427. doi: 10.1006/mcne.1999.0811. [PubMed] [Cross Ref]
7. Ghosh AK, Hong L, Tang J. β-Secretase as a therapeutic target for inhibitor drugs. Curr Med Chem. 2002;9:1135–1144. [PubMed]
8. Ghosh AK, Kumaragurubaran N, Tang J. Recent developments of structure based β-secretase inhibitors for Alzheimer’s disease. Curr Top Med Chem. 2005;5:1609–1622. doi: 10.2174/156802605775009711. [PubMed] [Cross Ref]
9. Thompson LA, Bronson JJ, Zusi FC. Progress in the discovery of BACE inhibitors. Curr Pharm Des. 2005;11:3383–3404. doi: 10.2174/138161205774370825. [PubMed] [Cross Ref]
10. John V. Human β-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem. 2006;6:569–578. doi: 10.2174/156802606776743084. [PubMed] [Cross Ref]
11. Durham TB, Shepherd TA. Progress toward the discovery and development of efficacious BACE inhibitors. Curr Opin Drug Discov Devel. 2006;9:776–791. [PubMed]
12. Hills ID, Vacca JP. Progress toward a practical BACE-1 inhibitor. Curr Opin Drug Discov Devel. 2007;10:383–391. [PubMed]
13. Cai H, Wang Y, McCarthy D, et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci. 2001;4:233–234. doi: 10.1038/85064. [PubMed] [Cross Ref]
14. Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat Neurosci. 2001;4:231–232. doi: 10.1038/85059. [PubMed] [Cross Ref]
15. Roberds SL, Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet. 2001;10:1317–1324. doi: 10.1093/hmg/10.12.1317. [PubMed] [Cross Ref]
16. Ohno M, Sametsky EA, Younkin LH, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron. 2004;41:27–33. doi: 10.1016/S0896-6273(03)00810-9. [PubMed] [Cross Ref]
17. Harrison SM, Harper AJ, Hawkins J, et al. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci. 2003;24:646–655. doi: 10.1016/S1044-7431(03)00227-6. [PubMed] [Cross Ref]
18. Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science. 2006;314:664–666. doi: 10.1126/science.1132341. [PubMed] [Cross Ref]
19. Hu X, Hicks CW, He W, et al. Bacel modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520–1525. doi: 10.1038/nn1797. [PubMed] [Cross Ref]
20. Sankaranarayanan S, Rice EA, Wu G, et al. In vivo beta-secretase 1 inhibition leads to brain Aβ lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol Exp Ther. 2008;324:957–969. doi: 10.1124/jpet.107.130039. [PubMed] [Cross Ref]
21. Chang WP, Koelsch G, Wong S, et al. In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors. J Neurochem. 2004;89:1409–1416. doi: 10.1111/j.1471-4159.2004.02452.x. [PubMed] [Cross Ref]
22. Chang WP, Downs D, Huang XP, Da H, Fung KM, Tang J. Amyloid-β reduction by memapsin 2 (β-secretase) immunization. FASEB J. 2007;21:3184–3196. doi: 10.1096/fj.06-7993com. [PubMed] [Cross Ref]
23. McConlogue L, Buttini M, Anderson JP, et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem. 2007;282:26326–26334. doi: 10.1074/jbc.M611687200. [PubMed] [Cross Ref]
24. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci. 2007;8:499–509. doi: 10.1038/nrn2168. [PubMed] [Cross Ref]
25. Turner RT, Hong L, Koelsch G, Ghosh AK, Tang J. Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (β-secretase) Biochemistry. 2005;44:105–112. doi: 10.1021/bi048106k. [PubMed] [Cross Ref]
26. Turner RT, Koelsch G, Hong L, et al. Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry. 2001;40:10001–10006. doi: 10.1021/bi015546s. [PubMed] [Cross Ref]
27. Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science. 2000;290:150–153. doi: 10.1126/science.290.5489.150. [PubMed] [Cross Ref]
28. Hong L, Turner RT, Koelsch G, Shin D, Ghosh AK, Tang J. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochemistry. 2002;41:10963–10967. doi: 10.1021/bi026232n. [PubMed] [Cross Ref]
29. Martin C, Sönnerborg A, Svensson JO, Ståhle L. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS. 1999;13:1227–1232. doi: 10.1097/00002030-199907090-00012. [PubMed] [Cross Ref]
30. Turner RT, Loy JA, Nguyen C, et al. Specificity of memapsin 1 and its implications on the design of memapsin 2 (β-secretase) inhibitor selectivity. Biochemistry. 2002;41:8742–8746. doi: 10.1021/bi025926t. [PubMed] [Cross Ref]
31. Marciniszyn J, Hartsuck JA, Tang J. Mode of inhibition of acid proteases by pepstatin. J Biol Chem. 1976;251:7088–7094. [PubMed]
32. Ghosh AK, Shin D, Downs B, Koelsch G, Lin X, Ermolieff J, Tang J. Design of potent inhibitors for human brain memapsin 2 (β-secretase) J Am Chem Soc. 2000;122:3522–3523. doi: 10.1021/ja000300g. [Cross Ref]
33. Ghosh AK, Koelsch G, Hong L, Huang X, Chang W, Tang J. Memapsin 2 (β-secretase) inhibitor GRL-8234 rescued cognitive decline of transgenic AD mice Tg2576. Presented at 4th International Conference of Alzheimer’s Disease, Ziirs, Austria 2007:50. (Abstract.)
34. Ghosh AK, Bilcer G, Harwood C, et al. Structure-based design: potent inhibitors of human brain memapsin 2 (β-secretase) J Med Chem. 2001;44:2865–2868. doi: 10.1021/jm0101803. [PubMed] [Cross Ref]
35. Ghosh AK, Kumaragurubaran N, Hong L, et al. Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (β-secretase) inhibitors. J Am Chem Soc. 2006;128:5310–5311. doi: 10.1021/ja058636j. [PMC free article] [PubMed] [Cross Ref]
36. Ghosh AK, Devasamudram T, Hong L, et al. Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase) Bioorg Med Chem Lett. 2005;15:15–20. doi: 10.1016/j.bmcl.2004.10.084. [PubMed] [Cross Ref]
37. Ghosh AK, Kumaragurubaran N, Hong L, et al. Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem. 2007;50:2399–2407. doi: 10.1021/jm061338s. [PubMed] [Cross Ref]
38. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci. 2001;21:372–381. [PubMed]
39. Kimura T, Hamada Y, Stochaj M, et al. Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1’ carboxylic acid bioisosteres. Bioorg Med Chem Lett. 2006;16:2380–2386. doi: 10.1016/j.bmcl.2006.01.108. [PubMed] [Cross Ref]
40. Hamada Y, Igawa N, Ikari H, et al. beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells. Bioorg Med Chem Lett. 2006;16:4354–4359. doi: 10.1016/j.bmcl.2006.05.046. [PubMed] [Cross Ref]
41. Maillard MC, Hom RK, Benson TE, et al. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase. J Med Chem. 2007;50:776–781. doi: 10.1021/jm061242y. [PubMed] [Cross Ref]
42. Kortum SW, Benson TE, Bienkowski MJ, et al. Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1. Bioorg Med Chem Lett. 2007;17:3378–3383. doi: 10.1016/j.bmcl.2007.03.096. [PubMed] [Cross Ref]
43. Freskos JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human beta-secretase. Part 1. Bioorg Med Chem Lett. 2007;17:73–77. doi: 10.1016/j.bmcl.2006.09.092. [PubMed] [Cross Ref]
44. Freskos JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human beta-secretase. Part 2. Bioorg Med Chem Lett. 2007;17:78–81. doi: 10.1016/j.bmcl.2006.09.091. [PubMed] [Cross Ref]
45. Hussain I, Hawkins J, Harrison D, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo. J Neurochem. 2007;100:802–809. doi: 10.1111/j.1471-4159.2006.04260.x. [PubMed] [Cross Ref]
46. Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs) Bioorg Med Chem Lett. 2008;18:1011–1016. doi: 10.1016/j.bmcl.2007.12.017. [PubMed] [Cross Ref]
47. Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett. 2008;18:1017–1021. doi: 10.1016/j.bmcl.2007.12.019. [PubMed] [Cross Ref]
48. Beswick P, Charrier N, Clarke B, et al. BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett. 2008;18:1022–1026. doi: 10.1016/j.bmcl.2007.12.020. [PubMed] [Cross Ref]
49. Rajapakse HA, Nantermet PG, Selnick HG, et al. Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1) J Med Chem. 2006;49:7270–7273. doi: 10.1021/jm061046r. [PubMed] [Cross Ref]
50. Lindsley SR, Moore KP, Rajapakse HA, et al. Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem Lett. 2007;17:4057–4061. doi: 10.1016/j.bmcl.2007.04.072. [PubMed] [Cross Ref]
51. Stachel SJ, Cobum CA, Sankaranarayanan S, et al. Macrocyclic inhibitors of beta-secretase: functional activity in an animal model. J Med Chem. 2006;49:6147–6150. doi: 10.1021/jm060884i. [PubMed] [Cross Ref]
52. Stauffer SR, Stanton MG, Gregro AR, et al. Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett. 2007;17:1788–1792. doi: 10.1016/j.bmcl.2006.12.051. [PubMed] [Cross Ref]
53. Stanton MG, Stauffer SR, Gregro AR, et al. Discovery of isonicotinamide derived beta-secretase inhibitors: in vivo reduction of beta-amyloid. J Med Chem. 2007;50:3431–3433. doi: 10.1021/jm070272d. [PubMed] [Cross Ref]
54. Cole DC, Manas ES, Stock JR, et al. Acylguanidines as small-molecule beta-secretase inhibitors. J Med Chem. 2006;49:6158–6161. doi: 10.1021/jm0607451. [PubMed] [Cross Ref]
55. Fobare WF, Solvibile WR, Robichaud AJ, et al. Thiophene substituted acylguanidines as BACE1 inhibitors. Bioorg Med Chem Lett. 2007;17:5353–5356. doi: 10.1016/j.bmcl.2007.08.010. [PubMed] [Cross Ref]
56. Cole DC, Stock JR, Chopra R, et al. Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets. Bioorg Med Chem Lett. 2008;18:1063–1066. doi: 10.1016/j.bmcl.2007.12.010. [PubMed] [Cross Ref]
57. Jennings LD, Cole DC, Stock JR, et al. Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1′ substrate binding pocket. Bioorg Med Chem Lett. 2008;18:767–771. doi: 10.1016/j.bmcl.2007.11.043. [PubMed] [Cross Ref]
58. Baxter EW, Conway KA, Kennis L, et al. 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead. J Med Chem. 2007;50:4261–4264. doi: 10.1021/jm0705408. [PubMed] [Cross Ref]
59. Rakover I, Arbel M, Solomon B. Immunotherapy against APP β-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain aβ levels. Neurodegener Dis. 2007;4:392–402. doi: 10.1159/000103250. [PubMed] [Cross Ref]
60. He X, Cooley K, Chung CH, Dashti N, Tang J. Apolipoprotein receptor 2 and X11 αβ mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production. J Neurosci. 2007;27:4052–4060. doi: 10.1523/JNEUROSCI.3993-06.2007. [PubMed] [Cross Ref]
61. He X, Li F, Chang WP, Tang J. GGA proteins mediate the recycling pathway of memapsin 2 (BACE) J Biol Chem. 2005;280:11696–11703. doi: 10.1074/jbc.M411296200. [PubMed] [Cross Ref]
62. He X, Chang WP, Koelsch G, Tang J. Memapsin 2 (β-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2 [Erratum in: FEBS Lett 2002;526:152] FEBS Lett. 2002;524:183–187. [PubMed]
63. He X, Zhu G, Koelsch G, Rodgers KK, Zhang XC, Tang J. Biochemical and structural characterization of the interaction of memapsin 2 (β-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry. 2003;42:12174–12180. doi: 10.1021/bi035199h. [PubMed] [Cross Ref]
64. Tesco G, Koh YH, Kang EL, et al. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron. 2007;54:721–737. doi: 10.1016/j.neuron.2007.05.012. [PMC free article] [PubMed] [Cross Ref]
65. Wahle T, Thal DR, Sastre M, et al. GGAl is expressed in the human brain and affects the generation of amyloid β-peptide. J Neurosci. 2006;26:12838–12846. doi: 10.1523/JNEUROSCI.1982-06.2006. [PubMed] [Cross Ref]
66. Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW. Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme; the Alzheimer’s disease β-secretase. J Biol Chem. 2000;275:33729–33737. doi: 10.1074/jbc.M004175200. [PubMed] [Cross Ref]
67. Pastorino L, Ikin AF, Nairn AC, Pursnani A, Buxbaum JD. The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total Aβ Mol Cell Neurosci. 2002;19:175–185. doi: 10.1006/mcne.2001.1065. [PubMed] [Cross Ref]

Articles from Neurotherapeutics are provided here courtesy of Springer