The discovery of β-secretase and development toward a clinical inhibitor for AD: An exciting academic collaboration

Aspartic Acid Proteases as Therapeutic Targets

Volumn 45, Issue , 2011, Pages 413-440

  Tang, Jordan ^a   Hong, Lin ^b   Ghosh, Arun K ^c  

^a UNIVERSITY OF OKLAHOMA   (United States)

^b CoMentis Inc ^*  (United States)

^c PURDUE UNIVERSITY   (United States)

Author keywords

Alzheimer Disease; Aspartyl proteases; BACE1 inhibitor; Blood brain barrier; Cathepsin D; Memapsin 2 inhibitors; Peptidomimetic inhibitors; secretase inhibitors

Indexed keywords

EID: 85017331546     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527630943.ch15     Document Type: Chapter

References (42)

1. Tang, J., Wolf, S., Caputto, R., and Trucco, R.E. (1959) Isolation and crystallization of gastricsin from human gastric juice. The Journal of Biological Chemistry, 234, 1174-1178.
2. Tang, J., Sepulveda, P.,Marciniszyn, J., Jr., Chen, K.C., Huang, W.Y., Tao, N., Liu, D., and Lanier, J.P. (1973) Amino acid sequence of porcine pepsin. Proceedings of the National Academy of Sciences of the United States of America, 70, 3437-3439.
3. Chen, K.C.and Tang, J. (1972) Amino acid sequence around the epoxide-reactive residues in pepsin. The Journal of Biological Chemistry, 247, 2566-2574.
4. Al-Janabi, J., Hartsuck, J.A., and Tang, J. (1972) Kinetics and mechanism of pepsinogen activation. The Journal of Biological Chemistry, 247, 4628-4632.
5. Marciniszyn, J., Jr.,Huang, J.S.,Hartsuck, J.A., and Tang, J. (1976) Mechanism of intramolecular activation of pepsinogen. Evidence for an intermediate delta and the involvement of the active site of pepsin in the intramolecular activation of pepsinogen. The Journal of Biological Chemistry, 251, 7095-7102.
6. Tang, J., James, M.N., Hsu, I.N., Jenkins, J.A., and Blundell, T.L. (1978) Structural evidence for gene duplication in the evolution of the acid proteases. Nature, 271, 618-621.
7. Marciniszyn, J., Jr., Hartsuck, J.A., and Tang, J. (1976) Mode of inhibition of acid proteases by pepstatin. The Journal of Biological Chemistry, 251, 7088-7094.
8. Lin, X., Loy, J.A., Sussman, F., and Tang, J. (1993) Conformational instability of the Nand C-terminal lobes of porcine pepsin in neutral and alkaline solutions. Protein Science, 2, 1383-1390.
9. Ido, E.,Han, H.P., Kezdy, F.J., and Tang, J. (1991) Kinetic studies of human immunodeficiency virus type 1 protease and its active-site hydrogen bond mutant A28S. The Journal of Biological Chemistry, 266, 24359-24366.
10. Lin, X., Tang, J., Koelsch, G., Monod, M., and Foundling, S. (1993) Recombinant canditropsin, an extracellular aspartic protease from yeast Candida tropicalis.Escherichia coli expression, purification, zymogen activation, and enzymic properties. The Journal of Biological Chemistry, 268, 20143-20147.
11. Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A., and Tang, J. (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 97, 1456-1460.
12. Hussain, I., Powell, D., Howlett, D.R., Tew, D.G., Meek, T.D., Chapman, C., Gloger, I.S., Murphy, K.E., Southan, C.D., Ryan, D.M., Smith, T.S., Simmons, D.L., Walsh, F.S., Dingwall, C., and Christie, G. (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Molecular and Cellular Neurosciences, 14, 419-427.
13. Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S.,Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G., and Citron, M. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286 735-741.
14. Yan, R., Bienkowski, M.J., Shuck, M.E., Miao, H., Tory, M.C., Pauley, A.M., Brashier, J.R., Stratman, N.C., Mathews, W.R., Buhl, A.E., Carter, D.B., Tomasselli, A.G., Parodi, L.A., Heinrikson, R.L., and Gurney, M.E. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature, 402, 533-537.
15. Sinha, S., Anderson, J.P., Barbour, R., Basi, G.S., Caccavello, R., Davis, D., Doan, M., Dovey, H.F., Frigon, N., Hong, J., Jacobson-Croak, K., Jewett, N., Keim, P., Knops, J., Lieberburg, I., Power, M., Tan, H., Tatsuno, G., Tung, J., Schenk, D., Seubert, P., Suomensaari, S.M., Wang, S., Walker, D., Zhao, J., Mc Conlogue, L., and John, V. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature, 402 537-540.
16. Ermolieff, J., Loy, J.A., Koelsch, G., and Tang, J. (2000) Proteolytic activation of recombinant pro-memapsin 2 (Pro-betasecretase) studied with new fluorogenic substrates. Biochemistry, 39, 16263.
17. Turner, R.T., 3rd, Koelsch, G., Hong, L., Castanheira, P., Ermolieff, J., Ghosh, A.K., and Tang, J. (2001) Subsite specificity of memapsin 2 (beta-secretase): implications for inhibitor design. Biochemistry, 40, 10001-10006.
18. Turner, R.T., 3rd, Loy, J.A., Nguyen, C., Devasamudram, T., Ghosh, A.K., Koelsch, G., and Tang, J. (2002) Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity. Biochemistry, 41, 8742-8746.
19. Ghosh, A.K., Shin, D., Downs, D., Koelsch, G., Lin, X., Ermolieff, J., and Tang, J. (2000) Design of potent inhibitors for human brain memapsin 2 (beta-secretase). Journal of the American Chemical Society, 122, 3522-3523.
20. Hong, L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A.K., Zhang, C.C., and Tang, J. (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science, 290, 150-153.
21. Turner, R.T., 3rd, Hong, L., Koelsch, G., Ghosh, A.K., and Tang, J. (2004) Structural locations and functional roles of new subsites S5, S6 and S7 in memapsin 2. (beta-secretase). Biochemistry, 44, 105-112.
22. Hong, L.and Tang, J. (2004) Flap position of free memapsin 2 (beta-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry, 43, 4689-4695.
23. Ghosh, A.K., Bilcer, G., Harwood, C., Kawahama, R., Shin, D., Hussain, K.A., Hong, L., Loy, J.A., Nguyen, C., Koelsch, G., Ermolieff, J., and Tang, J. (2001) Structure-based design: potent inhibitors of human brain memapsin 2 (betasecretase). Journal of Medicinal Chemistry, 44, 2865-2868.
24. Ghosh, A.K. (2009) Harnessing nature's insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer's disease. Journal of Medicinal Chemistry, 52, 2163-2176.
25. Schwab, P., France, M.B., Ziller, J.W., and Grubbs, R.H. (1995) A Series of welldefined metathesis catalysts-synthesis of [RuCl2(1/4CHR0)(PR3)2] and its reactions. Angewandte Chemie (International Edition in English), 34, 2039-2041.
26. Ghosh, A.K., Devasamudram, T., Hong, L., De Zutter, C., Xu, X., Weerasena, V., Koelsch, G., Bilcer, G., and Tang, J. (2005) Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2. (beta-secretase). Bioorganic & Medicinal Chemistry Letters, 15, 15-20.
27. Ghosh, A.K., Hong, L., and Tang, J. (2002) Beta-secretase as a therapeutic target for inhibitor drugs. Current Medicinal Chemistry, 9, 1135-1144.
28. Ghosh, A.K., Kumaragurubaran, N., Hong, L., Lei, H., Hussain, K.A., Liu, C.F., Devasamudram, T.,Weerasena, V., Turner, R., Koelsch, G., Bilcer, G., and Tang, J. (2006) Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors. Journal of the American Chemical Society, 128, 5310-5311.
29. Ghosh, A.K., Bilcer, G., Hong, L., Koelsch, G., and Tang, J. (2007) Memapsin 2 (betasecretase) inhibitor drug: between fantasy and reality. Current Alzheimer Research, 4, 418-422.
30. Maillard, M.C., Hom, R.K., Benson, T.E., Moon, J.B., Mamo, S., Bienkowski, M., Tomasselli, A.G., Woods, D.D., Prince, D.B., Paddock, D.J., Emmons, T.L., Tucker, J.A., Dappen, M.S., Brogley, L., Thorsett, E.D., Jewett, N., Sinha, S., and John, V. (2007) Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human b-secretase. Journal of Medicinal Chemistry, 50, 776.
31. Stachel, S.J., Coburn, C.A., Steele, T.G., Jones, K.G., Loutzenhiser, E.F., Gregro, A.R., Rajapakse, H.A., Lai, Ming-Tain, Crouthamel, M.-C., Xu, M., Tugusheva, K., Lineberger, J.E., Pietrak, B.L., Espeseth, A.S., Shi, X.-P., Chen-Dodson, E., Holloway, M.K., Munshi, S., Simon, A.J., Kuo, L., and Vacca, J.P. Structure-based design of potent and selective cellpermeable inhibitors of human b-secretase (BACE-1). (2004) Journal of Medicinal Chemistry, 47, 6447, and references cited therein.
32. Ghosh, A.K., Kumaragurubaran, N., Hong, L.,Kulkarni, S.S., Xu, X., Chang,W., Weerasena, V., Turner, R., Koelsch, G., Bilcer, G., and Tang, J. (2007) Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. Journal of Medicinal Chemistry, 50, 2399-2407.
33. Ghosh, A.K., Kumaragurubaran, N., Hong, L., Kulkarni, S., Xu, X., Miller, H.B., Reddy, D.S., Weerasena, V., Turner, R., Chang,W., Koelsch, G., and Tang, J. (2008) Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorganic & Medicinal Chemistry Letters, 18, 1031-1036.
34. Ghosh, A.K., Kumaragurubaran, N., Hong, L., Koelsch, G., and Tang, J. (2008) Memapsin 2 (beta-secretase) inhibitors: drug development. Current Alzheimer Research, 5, 121-131.
35. Ghosh, A.K., Gemma, S., and Tang, J. (2008) Beta-secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics, 5, 399-408.
36. http://www.athenagen.com/ index.php?/athenagen/press_releases/48.
37. Hey, J.A., Koelsch, G., Bilcer, G., Jacobs, A., Tolar, M., Tang, J., Ghosh, A.K., and Hsu, H.H. (2008) Single dose administration of the b-secretase inhibitor CTS21166 (ASP1702) reduces plasma Ab40 in human subjects. International Conference on Alzheimer's Disease (ICAD), Chicago, IL;
38. Hsu, H.H., Jacobs, A., Yu, J., Li, A., Koelsch, G., Bilcer, G., Tolar, M.,Grove, C.,Ghosh, A.K., Tang, J., and Hey, J.A. (2008) Phase 1 safety and pharmacokinetic profile of single doses of CTS21166 (ASP1702) in healthy males. International Conference on Alzheimer's Disease (ICAD), Chicago, IL;
39. Yu, J., Li, A., Koelsch, G., Bilcer, G., Hsu, H.H., Jacobs, A., Tolar, M., Tang, J., Ghosh, A.K., and Hey, J.A. (2008) Pharmacokinetic/ pharmacodynamic analysis of plasma Ab40 reduction in human subjects produced by the b-secretase inhibitor CTS21166 (ASP1702). International Conference on Alzheimer's Disease (ICAD), Chicago, IL;
40. Koelsch, G., Tang, J., Ghosh, A.K., Bilcer, G., Hey, J.A., and Windisch, M. (2008) BACE1 inhibitor CTS21166 (ASP1702) penetrates brain and reduces Ab pathology in a transgenic mouse model of advanced AD. International Conference on Alzheimer's Disease (ICAD), Chicago, IL;
41. Bilcer, G., Koelsch, G., Swanson, L., Yu, J., Li, A., Turner, R., Weerasena, V., Dehdarani, M., Tang, J., Ghosh, A.K., and Hey, J.A. (2008) Pharmacological profile of BACE1 inhibitor CTS21166 (ASP1702) International Conference on Alzheimer's Disease (ICAD), Chicago, IL;
42. Shitaka, Y., Yarimizu, J., Nagakura, A., Mitani, Y., Takami, S., Miyake, A., Hamakawa, N., Hey, J.A., Koelsch, G., Bilcer, G., and Matsuoka, N. (2008) Oral administration of the BACE1 inhibitor CTS21166 (ASP1702) improves cognition and reduces brain Ab in Tg2576 transgenic mice. International Conference on Alzheimer's Disease (ICAD), Chicago, IL.