Glutaminyl Cyclase Enzyme and Inhibitors
Keywords:
Alzheimer's, Amyloid Beta, Glutaminyl cyclase enzyme, Pyroglutamate modification, VaroglutamstatAbstract
The human glutaminyl cyclase enzyme (hQC) is an important enzyme that catalyzes pyroglutamate modification. QC secreted from hQC, which has two isoforms, is an enzyme that catalyzes pyroglutamate modification. N-Terminal pyroglutamate (pE) modification is an important post-translational event in mammals. The pE modification catalyzed by QC is a necessary modification for the maturation and function of many proteins and peptides. However, studies have shown that the increase in the amount of QC is associated with some diseases. With the abnormal increase in the secretion of QC, Alzheimer's (AD), Huntington's disease (HD), melanomas, thyroid carcinomas, rapid formation of atherosclerosis, septic arthritis occur. With this abnormal increase, the increase in pE-amyloid beta (Aβ) and pE-chemokine ligand (CCL2) formation resulting from pE modification catalyzed by QC may cause various pathologies. Only four drugs, including acetylcholinesterase (AchE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, are used for the clinical treatment of AD, a chronic neurodegenerative disease. These drugs relieve some symptoms for a limited time. Current drugs do not have any effects on stopping or slowing the progression of AD. Considering the consequences of abnormal secretion of QC and predisposing to the formation of diseases, it was aimed to reduce the formation of pE-modified mediators by inhibiting QC. The discovery of new drugs to inhibit QC is considered an important approach for the prevention and treatment of many physiological problems and diseases, including AD, inflammation, cancer. Therefore, it was thought that these pathological conditions could be prevented by QC inhibition, and various QC inhibitors were developed to combat it. In this review, various QC inhibitors, and their molecular structures, activities and also possible treatment options were examined. Extensive research has been done on varoglutamstat, which is in phase 2 of clinical trials, and QC inhibitors in general are summarized.
References
1. Xu C, Wang Y-n, Wu H. Glutaminyl cyclase, diseases, and development of glutaminyl cyclase inhibitors. Journal of Medicinal Chemistry. 2021;64(10):6549-65.
2. Schilling S, Manhart S, Hoffmann T, Ludwig H-H, Wasternack C, Demuth H-U. Substrate specificity of glutaminyl cyclases from plants and animals. 2003.
3. Azarkan M, Wintjens R, Looze Y, Baeyens-Volant D. Detection of three wound-induced proteins in papaya latex. Phytochemistry. 2004;65(5):525-34.
4. Messer M. Enzymatic cyclization of L-glutamine and L-glutaminyl peptides. Nature. 1963;197(4874):1299-.
5. Böckers TM, Kreutz MR, Pohl T. Glutaminyl‐cyclase expression in the bovine/porcine hypothalamus and pituitary. Journal of neuroendocrinology. 1995;7(6):445-53.
6. Wang Y-M, Huang K-F, Tsai I-H. Snake venom glutaminyl cyclases: Purification, cloning, kinetic study, recombinant expression, and comparison with the human enzyme. Toxicon. 2014;86:40-50.
7. Vijayasarathy M, Basheer SM, Balaram P. Cone snail glutaminyl cyclase sequences from transcriptomic analysis and mass spectrometric characterization of two pyroglutamyl conotoxins. Journal of proteome research. 2018;17(8):2695-703.
8. Sykes PA, Watson SJ, Temple JS, Bateman Jr RC. Evidence for tissue-specific forms of glutaminyl cyclase. FEBS letters. 1999;455(1-2):159-61.
9. Huang W-L, Wang Y-R, Ko T-P, Chia C-Y, Huang K-F, Wang AH-J. Crystal structure and functional analysis of the glutaminyl cyclase from Xanthomonas campestris. Journal of molecular biology. 2010;401(3):374-88.
10. Oberg KA, Ruysschaert JM, Azarkan M, Smolders N, Zerhouni S, Wintjens R, et al. Papaya glutamine cyclase, a plant enzyme highly resistant to proteolysis, adopts an all‐β conformation. European journal of biochemistry. 1998;258(1):214-22.
11. Wintjens R, Belrhali H, Clantin B, Azarkan M, Bompard C, Baeyens-Volant D, et al. Crystal structure of papaya glutaminyl cyclase, an archetype for plant and bacterial glutaminyl cyclases. Journal of molecular biology. 2006;357(2):457-70.
12. Pohl T, Zimmer M, Mugele K, Spiess J. Primary structure and functional expression of a glutaminyl cyclase. Proceedings of the National Academy of Sciences. 1991;88(22):10059-63.
13. Schilling S, Hoffmann T, Rosche F, Manhart S, Wasternack C, Demuth H-U. Heterologous expression and characterization of human glutaminyl cyclase: evidence for a disulfide bond with importance for catalytic activity. Biochemistry. 2002;41(35):10849-57.
14. Schilling S, Niestroj AJ, Rahfeld J-U, Hoffmann T, Wermann M, Zunkel K, et al. Identification of human glutaminyl cyclase as a metalloenzyme: Potent inhibition by imidazole derivatives and heterocyclic chelators. Journal of Biological Chemistry. 2003;278(50):49773-9.
15. Cynis H, Rahfeld J-U, Stephan A, Kehlen A, Koch B, Wermann M, et al. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. Journal of molecular biology. 2008;379(5):966-80.
16. Stephan A, Wermann M, von Bohlen A, Koch B, Cynis H, Demuth HU, et al. Mammalian glutaminyl cyclases and their isoenzymes have identical enzymatic characteristics. The FEBS Journal. 2009;276(22):6522-36.
17. Huang K-F, Liaw S-S, Huang W-L, Chia C-Y, Lo Y-C, Chen Y-L, et al. Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. Journal of Biological Chemistry. 2011;286(14):12439-49.
18. Höfling C, Indrischek H, Höpcke T, Waniek A, Cynis H, Koch B, et al. Mouse strain and brain region-specific expression of the glutaminyl cyclases QC and isoQC. International Journal of Developmental Neuroscience. 2014;36:64-73.
19. Schilling S, Kohlmann S, Bäuscher C, Sedlmeier R, Koch B, Eichentopf R, et al. Glutaminyl cyclase knock-out mice exhibit slight hypothyroidism but no hypogonadism: implications for enzyme function and drug development. Journal of Biological Chemistry. 2011;286(16):14199-208.
20. Huang K-F, Liu Y-L, Cheng W-J, Ko T-P, Wang AH-J. Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. Proceedings of the National Academy of Sciences. 2005;102(37):13117-22.
21. Ruiz-Carrillo D, Koch B, Parthier C, Wermann M, Dambe T, Buchholz M, et al. Structures of glycosylated mammalian glutaminyl cyclases reveal conformational variability near the active center. Biochemistry. 2011;50(28):6280-8.
22. Vijayan DK, Zhang KY. Human glutaminyl cyclase: Structure, function, inhibitors and involvement in Alzheimer’s disease. Pharmacological research. 2019;147:104342.
23. Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic acids research. 2014;42(W1):W320-W4.
24. Becker A, Eichentopf R, Sedlmeier R, Waniek A, Cynis H, Koch B, et al. IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes. Biological Chemistry. 2016;397(1):45-55.
25. Huang K-F, Liu Y-L, Wang AH-J. Cloning, expression, characterization, and crystallization of a glutaminyl cyclase from human bone marrow: a single zinc metalloenzyme. Protein expression and purification. 2005;43(1):65-72.
26. Huang K-F, Wang Y-R, Chang E-C, Chou T-L, Wang AH-J. A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis. Biochemical Journal. 2008;411(1):181-90.
27. DiPisa F, Pozzi C, Benvenuti M, Andreini M, Marconi G, Mangani S. The soluble Y115E–Y117E variant of human glutaminyl cyclase is a valid target for X-ray and NMR screening of inhibitors against Alzheimer disease. Acta Crystallographica Section F: Structural Biology Communications. 2015;71(8):986-92.
28. Pozzi C, Di Pisa F, Benvenuti M, Mangani S. The structure of the human glutaminyl cyclase–SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders. JBIC Journal of Biological Inorganic Chemistry. 2018;23(8):1219-26.
29. Seifert F, Demuth H-U, Weichler T, Ludwig H-H, Tittmann K, Schilling S. Phosphate ions and glutaminyl cyclases catalyze the cyclization of glutaminyl residues by facilitating synchronized proton transfers. Bioorganic chemistry. 2015;60:98-101.
30. Abraham GN, Podell DN. Pyroglutamic acid. Molecular and Cellular Biochemistry. 1981;38(1):181-90.
31. Hinke SA, Pospisilik JA, Demuth H-U, Mannhart S, Kühn-Wache K, Hoffmann T, et al. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon: characterization of glucagon degradation products and DPIV-resistant analogs. Journal of Biological Chemistry. 2000;275(6):3827-34.
32. Koshimizu H, Cawley NX, Yergy AL, Loh YP. Role of pGlu-serpinin, a novel chromogranin A-derived peptide in inhibition of cell death. Journal of Molecular Neuroscience. 2011;45(2):294-303.
33. Dana CM, Dotson‐Fagerstrom A, Roche CM, Kal SM, Chokhawala HA, Blanch HW, et al. The importance of pyroglutamate in cellulase Cel7A. Biotechnology and bioengineering. 2014;111(4):842-7.
34. Shih Y-P, Chou C-C, Chen Y-L, Huang K-F, Wang AH-J. Linked production of pyroglutamate-modified proteins via self-cleavage of fusion tags with TEV protease and autonomous N-terminal cyclization with glutaminyl cyclase in vivo. PLoS One. 2014;9(4):e94812.
35. Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth H-U. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS letters. 2004;563(1-3):191-6.
36. Jawhar S, Wirths O, Schilling S, Graubner S, Demuth H-U, Bayer TA. Overexpression of glutaminyl cyclase, the enzyme responsible for pyroglutamate Aβ formation, induces behavioral deficits, and glutaminyl cyclase knock-out rescues the behavioral phenotype in 5XFAD mice. Journal of Biological Chemistry. 2011;286(6):4454-60.
37. Kehlen A, Haegele M, Böhme L, Cynis H, Hoffmann T, Demuth H-U. N-terminal pyroglutamate formation in CX3CL1 is essential for its full biologic activity. Bioscience reports. 2017;37(4).
38. GOREN HJ, BAUCE LG, VALE W. Forces and structural limitations of binding of thyrotrophin-releasing factor to the thyrotrophin-releasing receptor: the pyroglutamic acid moiety. Molecular Pharmacology. 1977;13(4):606-14.
39. Gong J-H, Clark-Lewis I. Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. The Journal of experimental medicine. 1995;181(2):631-40.
40. Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, et al. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO molecular medicine. 2011;3(9):545-58.
41. Calvaresi M, Garavelli M, Bottoni A. Computational evidence for the catalytic mechanism of glutaminyl cyclase. A DFT investigation. Proteins: Structure, Function, and Bioinformatics. 2008;73(3):527-38.
42. Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology. Nature medicine. 2008;14(10):1106-11.
43. Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nature chemical biology. 2015;11(5):347-54.
44. Zhang Q-Q, Jiang T, Gu L-Z, Zhu X-C, Zhao H-D, Gao Q, et al. Common polymorphisms within QPCT gene are associated with the susceptibility of Schizophrenia in a Han Chinese population. Molecular neurobiology. 2016;53(9):6362-6.
45. Kehlen A, Haegele M, Menge K, Gans K, Immel U-D, Hoang-Vu C, et al. Role of glutaminyl cyclases in thyroid carcinomas. Endocrine-related cancer. 2013;20(1):79-90.
46. Ezura Y, Kajita M, Ishida R, Yoshida S, Yoshida H, Suzuki T, et al. Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene (QPCT) with low radial BMD in adult women. Journal of Bone and Mineral Research. 2004;19(8):1296-301.
47. Coimbra JR, Salvador JA. A patent review of glutaminyl cyclase inhibitors (2004-present). Expert Opinion on Therapeutic Patents. 2021(just-accepted).
48. Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, et al. β-amyloid is different in normal aging and in Alzheimer disease. Journal of Biological Chemistry. 2005;280(40):34186-92.
49. Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3 (pE), in senile plaques. Neuron. 1995;14(2):457-66.
50. Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D, et al. The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ. Acta neuropathologica communications. 2013;1(1):1-19.
51. Wu H. Can small molecule inhibitors of glutaminyl cyclase be used as a therapeutic for Alzheimer's disease? : Future Science; 2017. p. 1979-81.
52. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science. 2002;297(5580):353-6.
53. Cummings J, Aisen PS, DuBois B, Frölich L, Jack CR, Jones RW, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimer's research & therapy. 2016;8(1):1-12.
54. Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, et al. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry. 2009;48(29):7072-8.
55. Galante D, Corsaro A, Florio T, Vella S, Pagano A, Sbrana F, et al. Differential toxicity, conformation and morphology of typical initial aggregation states of Aβ1-42 and Aβpy3-42 beta-amyloids. The international journal of biochemistry & cell biology. 2012;44(11):2085-93.
56. Hosoda R, Saido TC, Otvos Jr L, Arai T, Mann DM, Lee VM-Y, et al. Quantification of modified amyloid β peptides in Alzheimer disease and Down syndrome brains. Journal of Neuropathology & Experimental Neurology. 1998;57(11):1089-95.
57. Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, et al. Pyroglutamate‐modified amyloid β‐peptides–AβN3 (pE)–strongly affect cultured neuron and astrocyte survival. Journal of neurochemistry. 2002;82(6):1480-9.
58. Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Böhm G, et al. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 2006;45(41):12393-9.
59. Casas C, Sergeant N, Itier J-M, Blanchard V, Wirths O, Van Der Kolk N, et al. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model. The American journal of pathology. 2004;165(4):1289-300.
60. Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease. Journal of Biological Chemistry. 2011;286(45):38825-32.
61. Antonios G, Saiepour N, Bouter Y, Richard BC, Paetau A, Verkkoniemi-Ahola A, et al. N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. Acta neuropathologica communications. 2013;1(1):1-15.
62. Harigaya Y, Saido TC, Eckman CB, Prada C-M, Shoji M, Younkin SG. Amyloid β protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochemical and biophysical research communications. 2000;276(2):422-7.
63. De Kimpe L, van Haastert ES, Kaminari A, Zwart R, Rutjes H, Hoozemans JJ, et al. Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome. Age. 2013;35(3):673-87.
64. Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature. 2012;485(7400):651-5.
65. Mandler M, Walker L, Santic R, Hanson P, Upadhaya AR, Colloby SJ, et al. Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease. Acta neuropathologica. 2014;128(1):67-79.
66. Valenti MT, Bolognin S, Zanatta C, Donatelli L, Innamorati G, Pampanin M, et al. Increased glutaminyl cyclase expression in peripheral blood of Alzheimer's disease patients. Journal of Alzheimer's Disease. 2013;34(1):263-71.
67. Bagyinszky E, Van Giau V, Shim K, Suk K, An SSA, Kim S. Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis. Journal of the neurological sciences. 2017;376:242-54.
68. Bose S, Cho J. Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Archives of pharmacal research. 2013;36(9):1039-50.
69. Kiyota T, Gendelman HE, Weir RA, Higgins EE, Zhang G, Jain M. CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease. Neurobiology of aging. 2013;34(4):1060-8.
70. Imarisio S, Carmichael J, Korolchuk V, Chen C-W, Saiki S, Rose C, et al. Huntington's disease: from pathology and genetics to potential therapies. Biochemical Journal. 2008;412(2):191-209.
71. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiological reviews. 2010;90(3):905-81.
72. Hinojosa AE, Garcia-Bueno B, Leza JC, Madrigal JL. CCL2/MCP-1 modulation of microglial activation and proliferation. Journal of neuroinflammation. 2011;8(1):1-10.
73. Hickman SE, Khoury JE. Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2010;9(2):168-73.
74. Conductier G, Blondeau N, Guyon A, Nahon J-L, Rovère C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of neuroimmunology. 2010;224(1-2):93-100.
75. Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, et al. CCL2 accelerates microglia-mediated Aβ oligomer formation and progression of neurocognitive dysfunction. PloS one. 2009;4(7):e6197.
76. Hartlage-Rübsamen M, Waniek A, Meißner J, Morawski M, Schilling S, Jäger C, et al. Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease. Acta neuropathologica. 2015;129(4):565-83.
77. Van Coillie E, Proost P, Van Aelst I, Struyf S, Polfliet M, De Meester I, et al. Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. Biochemistry. 1998;37(36):12672-80.
78. Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE. Monocyte chemoattractant protein‐1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease. Brain pathology. 2009;19(3):392-8.
79. El Khoury J, Luster AD. Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends in pharmacological sciences. 2008;29(12):626-32.
80. Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circulation research. 2004;95(9):858-66.
81. Inoshima I, Kuwano K, Hamada N, Hagimoto N, Yoshimi M, Maeyama T, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2004;286(5):L1038-L44.
82. Galimberti D, Fenoglio C, Lovati C, Venturelli E, Guidi I, Corrà B, et al. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease. Neurobiology of aging. 2006;27(12):1763-8.
83. Azizi G, Khannazer N, Mirshafiey A. The potential role of chemokines in Alzheimer’s disease pathogenesis. American Journal of Alzheimer's Disease & Other Dementias®. 2014;29(5):415-25.
84. Severini C, Passeri PP, Ciotti M, Florenzano F, Possenti R, Zona C, et al. Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity. Journal of Alzheimer's Disease. 2014;38(2):281-93.
85. Azizi G, Navabi SS, Al-Shukaili A, Seyedzadeh MH, Yazdani R, Mirshafiey A. The role of inflammatory mediators in the pathogenesis of Alzheimer’s disease. Sultan Qaboos University Medical Journal. 2015;15(3):e305.
86. Naert G, Rivest S. A deficiency in CCR2+ monocytes: the hidden side of Alzheimer's disease. Journal of molecular cell biology. 2013;5(5):284-93.
87. Willingham SB, Volkmer J-P, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences. 2012;109(17):6662-7.
88. Barclay AN, Van den Berg TK. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annual review of immunology. 2014;32:25-50.
89. Wu Z, Weng L, Zhang T, Tian H, Fang L, Teng H, et al. Identification of glutaminyl cyclase isoenzyme isoQC as a regulator of SIRPα-CD47 axis. Cell research. 2019;29(6):502-5.
90. Logtenberg ME, Jansen J, Raaben M, Toebes M, Franke K, Brandsma AM, et al. Glutaminyl cyclase is an enzymatic modifier of the CD47-SIRPα axis and a target for cancer immunotherapy. Nature medicine. 2019;25(4):612-9.
91. Sockolosky JT, Dougan M, Ingram JR, Ho CCM, Kauke MJ, Almo SC, et al. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proceedings of the National Academy of Sciences. 2016;113(19):E2646-E54.
92. Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN. Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47. Molecular cell. 2008;31(2):266-77.
93. Burgess TL, Amason JD, Rubin JS, Duveau DY, Lamy L, Roberts DD, et al. A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology. PloS one. 2020;15(4):e0226661.
94. de Molon RS, Rossa Jr C, Thurlings RM, Cirelli JA, Koenders MI. Linkage of periodontitis and rheumatoid arthritis: current evidence and potential biological interactions. International journal of molecular sciences. 2019;20(18):4541.
95. Mei F, Xie M, Huang X, Long Y, Lu X, Wang X, et al. Porphyromonas gingivalis and its systemic impact: Current status. Pathogens. 2020;9(11):944.
96. Bender P, Egger A, Westermann M, Taudte N, Sculean A, Potempa J, et al. Expression of human and Porphyromonas gingivalis glutaminyl cyclases in periodontitis and rheumatoid arthritis–A pilot study. Archives of oral biology. 2019;97:223-30.
97. Taudte N, Linnert M, Rahfeld J-U, Piechotta A, Ramsbeck D, Buchholz M, et al. Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis. Journal of Biological Chemistry. 2021;296.
98. Van Manh N, Hoang V-H, Ngo VT, Ann J, Jang T-H, Ha J-H, et al. Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design. European Journal of Medicinal Chemistry. 2021;226:113819.
99. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimer's research & therapy. 2021;13(1):1-3.
100. Mullard A. Anti-amyloid failures stack up as Alzheimer antibody flops. Nature reviews Drug discovery. 2019.
101. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nature Reviews Neurology. 2019;15(2):73-88.
102. Yang T, Li S, Xu H, Walsh DM, Selkoe DJ. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. Journal of Neuroscience. 2017;37(1):152-63.
103. Coimbra JR, Sobral PJ, Santos AE, Moreira PI, Salvador JA. An overview of glutaminyl cyclase inhibitors for Alzheimer’s disease. Future Medicinal Chemistry. 2019;11(24):3179-94.
104. Buchholz M, Heiser U, Schilling S, Niestroj AJ, Zunkel K, Demuth H-U. The first potent inhibitors for human glutaminyl cyclase: Synthesis and structure− activity relationship. Journal of medicinal chemistry. 2006;49(2):664-77.
105. Buchholz M, Hamann A, Aust S, Brandt W, Böhme L, Hoffmann T, et al. Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement. Journal of medicinal chemistry. 2009;52(22):7069-80.
106. Tran P-T, Hoang V-H, Thorat SA, Kim SE, Ann J, Chang YJ, et al. Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl) propyl thiourea template. Bioorganic & medicinal chemistry. 2013;21(13):3821-30.
107. Hoang V-H, Tran P-T, Cui M, Ngo VT, Ann J, Park J, et al. Discovery of potent human glutaminyl cyclase inhibitors as anti-Alzheimer’s agents based on rational design. Journal of medicinal chemistry. 2017;60(6):2573-90.
108. Ngo VT, Hoang V-H, Tran P-T, Van Manh N, Ann J, Kim E, et al. Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors. Bioorganic & Medicinal Chemistry. 2018;26(12):3133-44.
109. Ngo VT, Hoang V-H, Tran P-T, Ann J, Cui M, Park G, et al. Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer’s agents: Structure-activity relationship study of Arg-mimetic region. Bioorganic & medicinal chemistry. 2018;26(5):1035-49.
110. Busby Jr WH, Quackenbush GE, Humm J, Youngblood WW, Kizer J. An enzyme (s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. Journal of Biological Chemistry. 1987;262(18):8532-6.
111. Ramsbeck D, Buchholz M, Koch B, Böhme L, Hoffmann T, Demuth H-U, et al. Structure–activity relationships of benzimidazole-based glutaminyl cyclase inhibitors featuring a heteroaryl scaffold. Journal of Medicinal Chemistry. 2013;56(17):6613-25.
112. Lues I, Weber F, Meyer A, Bühring U, Hoffmann T, Kühn-Wache K, et al. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2015;1(3):182-95.
113. Hoffmann T, Meyer A, Heiser U, Kurat S, Böhme L, Kleinschmidt M, et al. Glutaminyl cyclase inhibitor PQ912 improves cognition in mouse models of Alzheimer’s disease—studies on relation to effective target occupancy. Journal of Pharmacology and Experimental Therapeutics. 2017;362(1):119-30.
114. Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimer's research & therapy. 2018;10(1):1-14.
115. Li M, Dong Y, Yu X, Li Y, Zou Y, Zheng Y, et al. Synthesis and evaluation of diphenyl conjugated imidazole derivatives as potential glutaminyl cyclase inhibitors for treatment of Alzheimer’s disease. Journal of Medicinal Chemistry. 2017;60(15):6664-77.
116. Hoang V-H, Ngo VT, Cui M, Manh NV, Tran P-T, Ann J, et al. Discovery of conformationally restricted human glutaminyl cyclase inhibitors as potent anti-Alzheimer’s agents by structure-based design. Journal of medicinal chemistry. 2019;62(17):8011-27.
117. Dileep K, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, et al. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. International Journal of Biological Macromolecules. 2021;170:415-23.
118. Hielscher-Michael S, Griehl C, Buchholz M, Demuth H-U, Arnold N, Wessjohann LA. Natural products from microalgae with potential against Alzheimer’s disease: Sulfolipids are potent glutaminyl cyclase inhibitors. Marine drugs. 2016;14(11):203.
119. Li M, Dong Y, Yu X, Zou Y, Zheng Y, Bu X, et al. Inhibitory effect of flavonoids on human glutaminyl cyclase. Bioorganic & Medicinal Chemistry. 2016;24(10):2280-6.
120. Luccarini I, Grossi C, Rigacci S, Coppi E, Pugliese AM, Pantano D, et al. Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates. Neurobiology of Aging. 2015;36(2):648-63.
121. Briels C, Stam C, Scheltens P, Bruins S, Lues I, Gouw A. In pursuit of a sensitive EEG functional connectivity outcome measure for clinical trials in Alzheimer’s disease. Clinical Neurophysiology. 2020;131(1):88-95.
122. Vijverberg E, Axelsen T, Bihlet A, Henriksen K, Weber F, Fuchs K, et al. Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD—VIVIAD. Alzheimer's research & therapy. 2021;13(1):1-8.
123. Wu G, Miller RA, Connolly B, Marcus J, Renger J, Savage MJ. Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain. Neurodegenerative Diseases. 2014;14(2):53-66.
124. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. New England Journal of Medicine. 2021;384(18):1691-704.
125. Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. The Lancet Neurology. 2016;15(7):673-84.
126. Hoffmann T, Rahfeld J-U, Schenk M, Ponath F, Makioka K, Hutter-Paier B, et al. Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice. International journal of molecular sciences. 2021;22(21):11791.
127. Lowe SL, Willis BA, Hawdon A, Natanegara F, Chua L, Foster J, et al. Donanemab (LY3002813) dose‐escalation study in Alzheimer's disease. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2021;7(1):e12112.
128. Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, et al. Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. Journal of Biological Chemistry. 2012;287(11):8154-62.
129. Becker A, Kohlmann S, Alexandru A, Jagla W, Canneva F, Bäuscher C, et al. Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration. BMC neuroscience. 2013;14(1):1-18.
130. Hettmann T, Gillies SD, Kleinschmidt M, Piechotta A, Makioka K, Lemere CA, et al. Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation. Scientific reports. 2020;10(1):1-13.
131. Polanco JC, Li C, Bodea L-G, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity—towards improved biomarkers and targeted therapies. Nature Reviews Neurology. 2018;14(1):22-39.
132. Puzzo D, Gulisano W, Arancio O, Palmeri A. The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience. 2015;307:26-36.
133. Bayer TA, Wirths O. Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease. Acta neuropathologica. 2014;127(6):787-801.
134. Kupski O, Funk L-M, Sautner V, Seifert F, Worbs B, Ramsbeck D, et al. Hydrazides are potent transition-state analogues for glutaminyl cyclase implicated in the pathogenesis of Alzheimer’s disease. Biochemistry. 2020;59(28):2585-91.
2. Schilling S, Manhart S, Hoffmann T, Ludwig H-H, Wasternack C, Demuth H-U. Substrate specificity of glutaminyl cyclases from plants and animals. 2003.
3. Azarkan M, Wintjens R, Looze Y, Baeyens-Volant D. Detection of three wound-induced proteins in papaya latex. Phytochemistry. 2004;65(5):525-34.
4. Messer M. Enzymatic cyclization of L-glutamine and L-glutaminyl peptides. Nature. 1963;197(4874):1299-.
5. Böckers TM, Kreutz MR, Pohl T. Glutaminyl‐cyclase expression in the bovine/porcine hypothalamus and pituitary. Journal of neuroendocrinology. 1995;7(6):445-53.
6. Wang Y-M, Huang K-F, Tsai I-H. Snake venom glutaminyl cyclases: Purification, cloning, kinetic study, recombinant expression, and comparison with the human enzyme. Toxicon. 2014;86:40-50.
7. Vijayasarathy M, Basheer SM, Balaram P. Cone snail glutaminyl cyclase sequences from transcriptomic analysis and mass spectrometric characterization of two pyroglutamyl conotoxins. Journal of proteome research. 2018;17(8):2695-703.
8. Sykes PA, Watson SJ, Temple JS, Bateman Jr RC. Evidence for tissue-specific forms of glutaminyl cyclase. FEBS letters. 1999;455(1-2):159-61.
9. Huang W-L, Wang Y-R, Ko T-P, Chia C-Y, Huang K-F, Wang AH-J. Crystal structure and functional analysis of the glutaminyl cyclase from Xanthomonas campestris. Journal of molecular biology. 2010;401(3):374-88.
10. Oberg KA, Ruysschaert JM, Azarkan M, Smolders N, Zerhouni S, Wintjens R, et al. Papaya glutamine cyclase, a plant enzyme highly resistant to proteolysis, adopts an all‐β conformation. European journal of biochemistry. 1998;258(1):214-22.
11. Wintjens R, Belrhali H, Clantin B, Azarkan M, Bompard C, Baeyens-Volant D, et al. Crystal structure of papaya glutaminyl cyclase, an archetype for plant and bacterial glutaminyl cyclases. Journal of molecular biology. 2006;357(2):457-70.
12. Pohl T, Zimmer M, Mugele K, Spiess J. Primary structure and functional expression of a glutaminyl cyclase. Proceedings of the National Academy of Sciences. 1991;88(22):10059-63.
13. Schilling S, Hoffmann T, Rosche F, Manhart S, Wasternack C, Demuth H-U. Heterologous expression and characterization of human glutaminyl cyclase: evidence for a disulfide bond with importance for catalytic activity. Biochemistry. 2002;41(35):10849-57.
14. Schilling S, Niestroj AJ, Rahfeld J-U, Hoffmann T, Wermann M, Zunkel K, et al. Identification of human glutaminyl cyclase as a metalloenzyme: Potent inhibition by imidazole derivatives and heterocyclic chelators. Journal of Biological Chemistry. 2003;278(50):49773-9.
15. Cynis H, Rahfeld J-U, Stephan A, Kehlen A, Koch B, Wermann M, et al. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. Journal of molecular biology. 2008;379(5):966-80.
16. Stephan A, Wermann M, von Bohlen A, Koch B, Cynis H, Demuth HU, et al. Mammalian glutaminyl cyclases and their isoenzymes have identical enzymatic characteristics. The FEBS Journal. 2009;276(22):6522-36.
17. Huang K-F, Liaw S-S, Huang W-L, Chia C-Y, Lo Y-C, Chen Y-L, et al. Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. Journal of Biological Chemistry. 2011;286(14):12439-49.
18. Höfling C, Indrischek H, Höpcke T, Waniek A, Cynis H, Koch B, et al. Mouse strain and brain region-specific expression of the glutaminyl cyclases QC and isoQC. International Journal of Developmental Neuroscience. 2014;36:64-73.
19. Schilling S, Kohlmann S, Bäuscher C, Sedlmeier R, Koch B, Eichentopf R, et al. Glutaminyl cyclase knock-out mice exhibit slight hypothyroidism but no hypogonadism: implications for enzyme function and drug development. Journal of Biological Chemistry. 2011;286(16):14199-208.
20. Huang K-F, Liu Y-L, Cheng W-J, Ko T-P, Wang AH-J. Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. Proceedings of the National Academy of Sciences. 2005;102(37):13117-22.
21. Ruiz-Carrillo D, Koch B, Parthier C, Wermann M, Dambe T, Buchholz M, et al. Structures of glycosylated mammalian glutaminyl cyclases reveal conformational variability near the active center. Biochemistry. 2011;50(28):6280-8.
22. Vijayan DK, Zhang KY. Human glutaminyl cyclase: Structure, function, inhibitors and involvement in Alzheimer’s disease. Pharmacological research. 2019;147:104342.
23. Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic acids research. 2014;42(W1):W320-W4.
24. Becker A, Eichentopf R, Sedlmeier R, Waniek A, Cynis H, Koch B, et al. IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes. Biological Chemistry. 2016;397(1):45-55.
25. Huang K-F, Liu Y-L, Wang AH-J. Cloning, expression, characterization, and crystallization of a glutaminyl cyclase from human bone marrow: a single zinc metalloenzyme. Protein expression and purification. 2005;43(1):65-72.
26. Huang K-F, Wang Y-R, Chang E-C, Chou T-L, Wang AH-J. A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis. Biochemical Journal. 2008;411(1):181-90.
27. DiPisa F, Pozzi C, Benvenuti M, Andreini M, Marconi G, Mangani S. The soluble Y115E–Y117E variant of human glutaminyl cyclase is a valid target for X-ray and NMR screening of inhibitors against Alzheimer disease. Acta Crystallographica Section F: Structural Biology Communications. 2015;71(8):986-92.
28. Pozzi C, Di Pisa F, Benvenuti M, Mangani S. The structure of the human glutaminyl cyclase–SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders. JBIC Journal of Biological Inorganic Chemistry. 2018;23(8):1219-26.
29. Seifert F, Demuth H-U, Weichler T, Ludwig H-H, Tittmann K, Schilling S. Phosphate ions and glutaminyl cyclases catalyze the cyclization of glutaminyl residues by facilitating synchronized proton transfers. Bioorganic chemistry. 2015;60:98-101.
30. Abraham GN, Podell DN. Pyroglutamic acid. Molecular and Cellular Biochemistry. 1981;38(1):181-90.
31. Hinke SA, Pospisilik JA, Demuth H-U, Mannhart S, Kühn-Wache K, Hoffmann T, et al. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon: characterization of glucagon degradation products and DPIV-resistant analogs. Journal of Biological Chemistry. 2000;275(6):3827-34.
32. Koshimizu H, Cawley NX, Yergy AL, Loh YP. Role of pGlu-serpinin, a novel chromogranin A-derived peptide in inhibition of cell death. Journal of Molecular Neuroscience. 2011;45(2):294-303.
33. Dana CM, Dotson‐Fagerstrom A, Roche CM, Kal SM, Chokhawala HA, Blanch HW, et al. The importance of pyroglutamate in cellulase Cel7A. Biotechnology and bioengineering. 2014;111(4):842-7.
34. Shih Y-P, Chou C-C, Chen Y-L, Huang K-F, Wang AH-J. Linked production of pyroglutamate-modified proteins via self-cleavage of fusion tags with TEV protease and autonomous N-terminal cyclization with glutaminyl cyclase in vivo. PLoS One. 2014;9(4):e94812.
35. Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth H-U. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS letters. 2004;563(1-3):191-6.
36. Jawhar S, Wirths O, Schilling S, Graubner S, Demuth H-U, Bayer TA. Overexpression of glutaminyl cyclase, the enzyme responsible for pyroglutamate Aβ formation, induces behavioral deficits, and glutaminyl cyclase knock-out rescues the behavioral phenotype in 5XFAD mice. Journal of Biological Chemistry. 2011;286(6):4454-60.
37. Kehlen A, Haegele M, Böhme L, Cynis H, Hoffmann T, Demuth H-U. N-terminal pyroglutamate formation in CX3CL1 is essential for its full biologic activity. Bioscience reports. 2017;37(4).
38. GOREN HJ, BAUCE LG, VALE W. Forces and structural limitations of binding of thyrotrophin-releasing factor to the thyrotrophin-releasing receptor: the pyroglutamic acid moiety. Molecular Pharmacology. 1977;13(4):606-14.
39. Gong J-H, Clark-Lewis I. Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. The Journal of experimental medicine. 1995;181(2):631-40.
40. Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, et al. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO molecular medicine. 2011;3(9):545-58.
41. Calvaresi M, Garavelli M, Bottoni A. Computational evidence for the catalytic mechanism of glutaminyl cyclase. A DFT investigation. Proteins: Structure, Function, and Bioinformatics. 2008;73(3):527-38.
42. Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathology. Nature medicine. 2008;14(10):1106-11.
43. Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nature chemical biology. 2015;11(5):347-54.
44. Zhang Q-Q, Jiang T, Gu L-Z, Zhu X-C, Zhao H-D, Gao Q, et al. Common polymorphisms within QPCT gene are associated with the susceptibility of Schizophrenia in a Han Chinese population. Molecular neurobiology. 2016;53(9):6362-6.
45. Kehlen A, Haegele M, Menge K, Gans K, Immel U-D, Hoang-Vu C, et al. Role of glutaminyl cyclases in thyroid carcinomas. Endocrine-related cancer. 2013;20(1):79-90.
46. Ezura Y, Kajita M, Ishida R, Yoshida S, Yoshida H, Suzuki T, et al. Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene (QPCT) with low radial BMD in adult women. Journal of Bone and Mineral Research. 2004;19(8):1296-301.
47. Coimbra JR, Salvador JA. A patent review of glutaminyl cyclase inhibitors (2004-present). Expert Opinion on Therapeutic Patents. 2021(just-accepted).
48. Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, et al. β-amyloid is different in normal aging and in Alzheimer disease. Journal of Biological Chemistry. 2005;280(40):34186-92.
49. Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3 (pE), in senile plaques. Neuron. 1995;14(2):457-66.
50. Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D, et al. The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ. Acta neuropathologica communications. 2013;1(1):1-19.
51. Wu H. Can small molecule inhibitors of glutaminyl cyclase be used as a therapeutic for Alzheimer's disease? : Future Science; 2017. p. 1979-81.
52. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science. 2002;297(5580):353-6.
53. Cummings J, Aisen PS, DuBois B, Frölich L, Jack CR, Jones RW, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimer's research & therapy. 2016;8(1):1-12.
54. Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, et al. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry. 2009;48(29):7072-8.
55. Galante D, Corsaro A, Florio T, Vella S, Pagano A, Sbrana F, et al. Differential toxicity, conformation and morphology of typical initial aggregation states of Aβ1-42 and Aβpy3-42 beta-amyloids. The international journal of biochemistry & cell biology. 2012;44(11):2085-93.
56. Hosoda R, Saido TC, Otvos Jr L, Arai T, Mann DM, Lee VM-Y, et al. Quantification of modified amyloid β peptides in Alzheimer disease and Down syndrome brains. Journal of Neuropathology & Experimental Neurology. 1998;57(11):1089-95.
57. Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, et al. Pyroglutamate‐modified amyloid β‐peptides–AβN3 (pE)–strongly affect cultured neuron and astrocyte survival. Journal of neurochemistry. 2002;82(6):1480-9.
58. Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Böhm G, et al. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 2006;45(41):12393-9.
59. Casas C, Sergeant N, Itier J-M, Blanchard V, Wirths O, Van Der Kolk N, et al. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model. The American journal of pathology. 2004;165(4):1289-300.
60. Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease. Journal of Biological Chemistry. 2011;286(45):38825-32.
61. Antonios G, Saiepour N, Bouter Y, Richard BC, Paetau A, Verkkoniemi-Ahola A, et al. N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. Acta neuropathologica communications. 2013;1(1):1-15.
62. Harigaya Y, Saido TC, Eckman CB, Prada C-M, Shoji M, Younkin SG. Amyloid β protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochemical and biophysical research communications. 2000;276(2):422-7.
63. De Kimpe L, van Haastert ES, Kaminari A, Zwart R, Rutjes H, Hoozemans JJ, et al. Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome. Age. 2013;35(3):673-87.
64. Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature. 2012;485(7400):651-5.
65. Mandler M, Walker L, Santic R, Hanson P, Upadhaya AR, Colloby SJ, et al. Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease. Acta neuropathologica. 2014;128(1):67-79.
66. Valenti MT, Bolognin S, Zanatta C, Donatelli L, Innamorati G, Pampanin M, et al. Increased glutaminyl cyclase expression in peripheral blood of Alzheimer's disease patients. Journal of Alzheimer's Disease. 2013;34(1):263-71.
67. Bagyinszky E, Van Giau V, Shim K, Suk K, An SSA, Kim S. Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis. Journal of the neurological sciences. 2017;376:242-54.
68. Bose S, Cho J. Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Archives of pharmacal research. 2013;36(9):1039-50.
69. Kiyota T, Gendelman HE, Weir RA, Higgins EE, Zhang G, Jain M. CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease. Neurobiology of aging. 2013;34(4):1060-8.
70. Imarisio S, Carmichael J, Korolchuk V, Chen C-W, Saiki S, Rose C, et al. Huntington's disease: from pathology and genetics to potential therapies. Biochemical Journal. 2008;412(2):191-209.
71. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiological reviews. 2010;90(3):905-81.
72. Hinojosa AE, Garcia-Bueno B, Leza JC, Madrigal JL. CCL2/MCP-1 modulation of microglial activation and proliferation. Journal of neuroinflammation. 2011;8(1):1-10.
73. Hickman SE, Khoury JE. Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2010;9(2):168-73.
74. Conductier G, Blondeau N, Guyon A, Nahon J-L, Rovère C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of neuroimmunology. 2010;224(1-2):93-100.
75. Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, et al. CCL2 accelerates microglia-mediated Aβ oligomer formation and progression of neurocognitive dysfunction. PloS one. 2009;4(7):e6197.
76. Hartlage-Rübsamen M, Waniek A, Meißner J, Morawski M, Schilling S, Jäger C, et al. Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease. Acta neuropathologica. 2015;129(4):565-83.
77. Van Coillie E, Proost P, Van Aelst I, Struyf S, Polfliet M, De Meester I, et al. Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. Biochemistry. 1998;37(36):12672-80.
78. Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE. Monocyte chemoattractant protein‐1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease. Brain pathology. 2009;19(3):392-8.
79. El Khoury J, Luster AD. Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends in pharmacological sciences. 2008;29(12):626-32.
80. Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circulation research. 2004;95(9):858-66.
81. Inoshima I, Kuwano K, Hamada N, Hagimoto N, Yoshimi M, Maeyama T, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary fibrosis in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2004;286(5):L1038-L44.
82. Galimberti D, Fenoglio C, Lovati C, Venturelli E, Guidi I, Corrà B, et al. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease. Neurobiology of aging. 2006;27(12):1763-8.
83. Azizi G, Khannazer N, Mirshafiey A. The potential role of chemokines in Alzheimer’s disease pathogenesis. American Journal of Alzheimer's Disease & Other Dementias®. 2014;29(5):415-25.
84. Severini C, Passeri PP, Ciotti M, Florenzano F, Possenti R, Zona C, et al. Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity. Journal of Alzheimer's Disease. 2014;38(2):281-93.
85. Azizi G, Navabi SS, Al-Shukaili A, Seyedzadeh MH, Yazdani R, Mirshafiey A. The role of inflammatory mediators in the pathogenesis of Alzheimer’s disease. Sultan Qaboos University Medical Journal. 2015;15(3):e305.
86. Naert G, Rivest S. A deficiency in CCR2+ monocytes: the hidden side of Alzheimer's disease. Journal of molecular cell biology. 2013;5(5):284-93.
87. Willingham SB, Volkmer J-P, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences. 2012;109(17):6662-7.
88. Barclay AN, Van den Berg TK. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annual review of immunology. 2014;32:25-50.
89. Wu Z, Weng L, Zhang T, Tian H, Fang L, Teng H, et al. Identification of glutaminyl cyclase isoenzyme isoQC as a regulator of SIRPα-CD47 axis. Cell research. 2019;29(6):502-5.
90. Logtenberg ME, Jansen J, Raaben M, Toebes M, Franke K, Brandsma AM, et al. Glutaminyl cyclase is an enzymatic modifier of the CD47-SIRPα axis and a target for cancer immunotherapy. Nature medicine. 2019;25(4):612-9.
91. Sockolosky JT, Dougan M, Ingram JR, Ho CCM, Kauke MJ, Almo SC, et al. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proceedings of the National Academy of Sciences. 2016;113(19):E2646-E54.
92. Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN. Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47. Molecular cell. 2008;31(2):266-77.
93. Burgess TL, Amason JD, Rubin JS, Duveau DY, Lamy L, Roberts DD, et al. A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology. PloS one. 2020;15(4):e0226661.
94. de Molon RS, Rossa Jr C, Thurlings RM, Cirelli JA, Koenders MI. Linkage of periodontitis and rheumatoid arthritis: current evidence and potential biological interactions. International journal of molecular sciences. 2019;20(18):4541.
95. Mei F, Xie M, Huang X, Long Y, Lu X, Wang X, et al. Porphyromonas gingivalis and its systemic impact: Current status. Pathogens. 2020;9(11):944.
96. Bender P, Egger A, Westermann M, Taudte N, Sculean A, Potempa J, et al. Expression of human and Porphyromonas gingivalis glutaminyl cyclases in periodontitis and rheumatoid arthritis–A pilot study. Archives of oral biology. 2019;97:223-30.
97. Taudte N, Linnert M, Rahfeld J-U, Piechotta A, Ramsbeck D, Buchholz M, et al. Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis. Journal of Biological Chemistry. 2021;296.
98. Van Manh N, Hoang V-H, Ngo VT, Ann J, Jang T-H, Ha J-H, et al. Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design. European Journal of Medicinal Chemistry. 2021;226:113819.
99. Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimer's research & therapy. 2021;13(1):1-3.
100. Mullard A. Anti-amyloid failures stack up as Alzheimer antibody flops. Nature reviews Drug discovery. 2019.
101. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nature Reviews Neurology. 2019;15(2):73-88.
102. Yang T, Li S, Xu H, Walsh DM, Selkoe DJ. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. Journal of Neuroscience. 2017;37(1):152-63.
103. Coimbra JR, Sobral PJ, Santos AE, Moreira PI, Salvador JA. An overview of glutaminyl cyclase inhibitors for Alzheimer’s disease. Future Medicinal Chemistry. 2019;11(24):3179-94.
104. Buchholz M, Heiser U, Schilling S, Niestroj AJ, Zunkel K, Demuth H-U. The first potent inhibitors for human glutaminyl cyclase: Synthesis and structure− activity relationship. Journal of medicinal chemistry. 2006;49(2):664-77.
105. Buchholz M, Hamann A, Aust S, Brandt W, Böhme L, Hoffmann T, et al. Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement. Journal of medicinal chemistry. 2009;52(22):7069-80.
106. Tran P-T, Hoang V-H, Thorat SA, Kim SE, Ann J, Chang YJ, et al. Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl) propyl thiourea template. Bioorganic & medicinal chemistry. 2013;21(13):3821-30.
107. Hoang V-H, Tran P-T, Cui M, Ngo VT, Ann J, Park J, et al. Discovery of potent human glutaminyl cyclase inhibitors as anti-Alzheimer’s agents based on rational design. Journal of medicinal chemistry. 2017;60(6):2573-90.
108. Ngo VT, Hoang V-H, Tran P-T, Van Manh N, Ann J, Kim E, et al. Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors. Bioorganic & Medicinal Chemistry. 2018;26(12):3133-44.
109. Ngo VT, Hoang V-H, Tran P-T, Ann J, Cui M, Park G, et al. Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer’s agents: Structure-activity relationship study of Arg-mimetic region. Bioorganic & medicinal chemistry. 2018;26(5):1035-49.
110. Busby Jr WH, Quackenbush GE, Humm J, Youngblood WW, Kizer J. An enzyme (s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. Journal of Biological Chemistry. 1987;262(18):8532-6.
111. Ramsbeck D, Buchholz M, Koch B, Böhme L, Hoffmann T, Demuth H-U, et al. Structure–activity relationships of benzimidazole-based glutaminyl cyclase inhibitors featuring a heteroaryl scaffold. Journal of Medicinal Chemistry. 2013;56(17):6613-25.
112. Lues I, Weber F, Meyer A, Bühring U, Hoffmann T, Kühn-Wache K, et al. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2015;1(3):182-95.
113. Hoffmann T, Meyer A, Heiser U, Kurat S, Böhme L, Kleinschmidt M, et al. Glutaminyl cyclase inhibitor PQ912 improves cognition in mouse models of Alzheimer’s disease—studies on relation to effective target occupancy. Journal of Pharmacology and Experimental Therapeutics. 2017;362(1):119-30.
114. Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimer's research & therapy. 2018;10(1):1-14.
115. Li M, Dong Y, Yu X, Li Y, Zou Y, Zheng Y, et al. Synthesis and evaluation of diphenyl conjugated imidazole derivatives as potential glutaminyl cyclase inhibitors for treatment of Alzheimer’s disease. Journal of Medicinal Chemistry. 2017;60(15):6664-77.
116. Hoang V-H, Ngo VT, Cui M, Manh NV, Tran P-T, Ann J, et al. Discovery of conformationally restricted human glutaminyl cyclase inhibitors as potent anti-Alzheimer’s agents by structure-based design. Journal of medicinal chemistry. 2019;62(17):8011-27.
117. Dileep K, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, et al. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. International Journal of Biological Macromolecules. 2021;170:415-23.
118. Hielscher-Michael S, Griehl C, Buchholz M, Demuth H-U, Arnold N, Wessjohann LA. Natural products from microalgae with potential against Alzheimer’s disease: Sulfolipids are potent glutaminyl cyclase inhibitors. Marine drugs. 2016;14(11):203.
119. Li M, Dong Y, Yu X, Zou Y, Zheng Y, Bu X, et al. Inhibitory effect of flavonoids on human glutaminyl cyclase. Bioorganic & Medicinal Chemistry. 2016;24(10):2280-6.
120. Luccarini I, Grossi C, Rigacci S, Coppi E, Pugliese AM, Pantano D, et al. Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates. Neurobiology of Aging. 2015;36(2):648-63.
121. Briels C, Stam C, Scheltens P, Bruins S, Lues I, Gouw A. In pursuit of a sensitive EEG functional connectivity outcome measure for clinical trials in Alzheimer’s disease. Clinical Neurophysiology. 2020;131(1):88-95.
122. Vijverberg E, Axelsen T, Bihlet A, Henriksen K, Weber F, Fuchs K, et al. Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD—VIVIAD. Alzheimer's research & therapy. 2021;13(1):1-8.
123. Wu G, Miller RA, Connolly B, Marcus J, Renger J, Savage MJ. Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain. Neurodegenerative Diseases. 2014;14(2):53-66.
124. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. New England Journal of Medicine. 2021;384(18):1691-704.
125. Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. The Lancet Neurology. 2016;15(7):673-84.
126. Hoffmann T, Rahfeld J-U, Schenk M, Ponath F, Makioka K, Hutter-Paier B, et al. Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice. International journal of molecular sciences. 2021;22(21):11791.
127. Lowe SL, Willis BA, Hawdon A, Natanegara F, Chua L, Foster J, et al. Donanemab (LY3002813) dose‐escalation study in Alzheimer's disease. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2021;7(1):e12112.
128. Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, et al. Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. Journal of Biological Chemistry. 2012;287(11):8154-62.
129. Becker A, Kohlmann S, Alexandru A, Jagla W, Canneva F, Bäuscher C, et al. Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration. BMC neuroscience. 2013;14(1):1-18.
130. Hettmann T, Gillies SD, Kleinschmidt M, Piechotta A, Makioka K, Lemere CA, et al. Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation. Scientific reports. 2020;10(1):1-13.
131. Polanco JC, Li C, Bodea L-G, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity—towards improved biomarkers and targeted therapies. Nature Reviews Neurology. 2018;14(1):22-39.
132. Puzzo D, Gulisano W, Arancio O, Palmeri A. The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience. 2015;307:26-36.
133. Bayer TA, Wirths O. Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease. Acta neuropathologica. 2014;127(6):787-801.
134. Kupski O, Funk L-M, Sautner V, Seifert F, Worbs B, Ramsbeck D, et al. Hydrazides are potent transition-state analogues for glutaminyl cyclase implicated in the pathogenesis of Alzheimer’s disease. Biochemistry. 2020;59(28):2585-91.
Downloads
Published
2022-07-15
Issue
Section
Articles
License
The authors keep the copyrights of the published materials with them, but the authors are aggee to give an exclusive license to the publisher that transfers all publishing and commercial exploitation rights to the publisher. The puslisher then shares the content published in this journal under CC BY-NC-ND license.
How to Cite
Glutaminyl Cyclase Enzyme and Inhibitors. (2022). International Journal of Innovative Research and Reviews, 6(1), 59-75. http://www.injirr.com/index.php/injirr/article/view/107
