, Volume 5, Issue 3, pp 399–408 | Cite as

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

Review Article


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 


  1. 1.
    Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 1999;399(6738 Suppl): A23–31.PubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Ghosh AK, Hong L, Tang J. β-Secretase as a therapeutic target for inhibitor drugs. Curr Med Chem 2002;9: 1135–1144.PubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 9.
    Thompson LA, Bronson JJ, Zusi FC. Progress in the discovery of BACE inhibitors. Curr Pharm Des 2005;11: 3383–3404.CrossRefPubMedGoogle Scholar
  10. 10.
    John V. Human β-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem 2006;6: 569–578.CrossRefPubMedGoogle Scholar
  11. 11.
    Durham TB, Shepherd TA. Progress toward the discovery and development of efficacious BACE inhibitors. Curr Opin Drug Discov Devel 2006;9: 776–791.PubMedGoogle Scholar
  12. 12.
    Hills ID, Vacca JP. Progress toward a practical BACE-1 inhibitor. Curr Opin Drug Discov Devel 2007;10: 383–391.PubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 18.
    Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science 2006;314: 664–666.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci 2007;8: 499–509.CrossRefPubMedGoogle Scholar
  25. 25.
    Turner RT 3rd, 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Turner RT 3rd, Koelsch G, Hong L, et al. Subsite specificity of memapsin 2 (β-secretase): implications for inhibitor design. Biochemistry 2001;40: 10001–10006.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 28.
    Hong L, Turner RT 3rd, 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Turner RT 3rd, 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Marciniszyn J Jr, Hartsuck JA, Tang J. Mode of inhibition of acid proteases by pepstatin. J Biol Chem 1976;251: 7088–7094.PubMedGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.)Google Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 54.
    Cole DC, Manas ES, Stock JR, et al. Acylguanidines as small-molecule beta-secretase inhibitors. J Med Chem 2006;49: 6158–6161.CrossRefPubMedGoogle Scholar
  55. 55.
    Fobare WF, Solvibile WR, Robichaud AJ, et al. Thiophene substituted acylguanidines as BACE1 inhibitors. Bioorg Med Chem Lett 2007; 17: 5353–5356.CrossRefPubMedGoogle Scholar
  56. 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.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 64.
    Tesco G, Koh YH, Kang EL, et al. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron 2007;54: 721–737.CrossRefPubMedGoogle Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.CrossRefPubMedGoogle Scholar
  67. 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.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2008

Authors and Affiliations

  1. 1.Departments of Chemistry and Medicinal ChemistryPurdue UniversityWest Lafayette
  2. 2.Oklahoma Medical Research FoundationUniversity of Oklahoma Health Science CenterOklahoma City
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Science CenterOklahoma City
  4. 4.Protein Studies Research Program, MS 28Oklahoma Medical Research FoundationOklahoma City

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