GLP-1的N端修饰研究进展及其用于治疗II型糖尿病的应用前景

doi:10.5246/jcps.2015.11.090

摘要/Abstract

摘要：

胰高血糖素样肽-1(GLP-1)是一种人体内源性的肠促胰素, 具有极强的体内降血糖活性,但在血浆中易被二肽基肽酶IV(DPP-IV)迅速降解失活, 由于DPP-IV的酶切位点靠近GLP-1的N端, 因此对N端进行结构修饰, 可以延长GLP-1的体内降血糖活性。过去有关GLP-1的N端修饰研究中, 主要包括对His⁷、Ala⁸和Glu⁹的结构修饰以及一些其他的结构改造(包括GLP-1的缩短肽类似物、小分子受体激动剂等), 以期望在增强对DPP-IV酶降解耐受能力的同时, 保持较好的受体结合力与激动活性。至今为止, 用甘氨酸(Gly)或者α-氨基异丁酸(Aib)取代GLP-1的N端Ala⁸修饰策略已被用于II型糖尿病药物(Exenatide、Semaglutide、Albiglutide、Taspoglutide等)的临床研究中。本文具体描述已经报道的各类GLP-1的N端修饰研究工作进展, 并讨论其在II型糖尿病治疗药物研发中的应用前景。

关键词: GLP-1类似物, DPP-IV, N端修饰, II型糖尿病

Abstract:

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV (DPP-IV). To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity,by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His⁷, Ala⁸or Glu⁹ at the N-terminus of GLP-1 and some other modifications. Among them, Ala⁸ substitutions with glycine (Gly⁸) and α-aminoisobutyric acid (Aib⁸) have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.

Key words: GLP-1 analogues, DPP-IV, N-terminal modification, Type 2 diabetes

中图分类号:

R914

Supporting:

白晓辉, 牛有红, 熊德彩, 吴艳芬, 李云森. GLP-1的N端修饰研究进展及其用于治疗II型糖尿病的应用前景[J]. 中国药学(英文版), 2015, 24(11): 701-711.

Xiaohui Bai, Youhong Niu, Decai Xiong, Yanfen Wu, Yunsen Li. Advances of N-terminal modifications of GLP-1 and their applications for the treatment of type 2 diabetes[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(11): 701-711.

参考文献

[1] Orskov, C.; Bersani, M.; Johnsen, A.H.; Hojrup, P.; Holst, J.J. J. Biol. Chem. 1989, 264, 12826-12829.

[2] Orskov, C.; Holst, J.J.; Knuhtsen, S.; Baldissera, F.G.; Poulsen, S.S.; Nielsen, O.V. Endocrinology. 1986, 119, 1467-1475.

[3] Baggio, L.L.; Drucker, D.J. Gastroenterology. 2007, 132, 2131-2157.

[4] Thorens, B. Diabetes. Metab. 1995, 21, 311-318.

[5] Orskov, C. Diabetologia. 1992, 35, 701-711.

[6] Weir, G.C.; Mojsov, S.; Hendrick, G.K.; Habener, J.F. Diabetes. 1989, 38, 338-342.

[7] Mojsov, S.; Weir, G.C.; Habener, J.F. J. Clin. Invest. 1987, 79, 616-619.

[8] Yi, F.; Du, Q. J. Chin. Pharm. Sci. 2013, 22,7-27.

[9] Deacon, C.F.; Johnsen, A.H.; Holst, J.J. J. Clin. Endocrinol. Metab. 1995, 80, 952-957.

[10] Kieffer, T.J.; McIntosh, C.H.; Pederson, R.A. Endocrinol. 1995, 136, 3585-3596.

[11] Mentlein, R.; Gallwitz, B.; Schmidt, W.E. Eur. J. Biochem.1993, 214, 829-835.

[12] Hupe-Sodmann, K.; McGregor, G.P.; Bridenbaugh, R.; Goke, R.; Goke, B.; Thole, H.; Zimmermann, B.; Voigt, K. Regul. Peptide. 1995, 58, 149-156.

[13] Wettergren, A.; Pridal, L.; Wojdemann, M.; Holst, J.J. Regul. Peptide. 1998, 77, 83-87

[14] Holtmann, M.H.; Ganguli, S.; Hadac, E.M.; Dolu, V.; Miller, L.J. J. Biol. Chem. 1996, 271, 14944-14949.

[15] Dong, M.; Li, Z.; Zang, M.; Pinon, D.I.; Lybrand, T.P.; Miller, L.J. J. Biol. Chem. 2003, 278, 48300-48312.

[16] Lopez, D.M.R.; Willshaw, A.; Kuntzsch, A.; Rudolph, R.; Donnelly, D. J. Biol. Chem. 2003, 278, 10195-10200.

[17] Dong, M.; Li, Z.; Pinon, D.I.; Lybrand, T.P.; Miller, L.J. J. Biol. Chem. 2004, 279, 2894-2903.

[18] Runge, S.; Gram, C.; Brauner-Osborne, H.; Madsen, K.; Knudsen, L.B.; Wulff, B.S. J. Biol. Chem. 2003, 278, 28005-28010.

[19] Solano, R.M.; Langer, I.; Perret, J.; Vertongen, P.; Juarranz, M.G.; Robberecht, P.; Waelbroeck, M. J. Biol. Chem. 2001, 276, 1084-1088.

[20] Gallwitz, B.; Ropeter, T.; Morys-Wortmann, C.; Mentlein, R.; Siegel, E.G.; Schmidt, W.E. Regul. Peptide. 2000, 86, 103-111.

[21] O’Harte, F.P.; Gray, A.M.; Abdel-Wahab, Y.H.; Flatt, P.R. Peptides. 1997, 18, 1327-1333.

[22] O’Harte, F.P.; Mooney, M.H.; Lawlor, A.; Flatt, P.R. Biochim. Biophys. Acta. 2000, 1474, 13-22.

[23] O’Harte, F.P.; Mooney, M.H.; Kelly, C.M.; McKillop, A.M.; Flatt, P.R. Regul. Peptide. 2001, 96, 95-104.

[24] Green, B.D.; Mooney, M.H.; Gault, V.A.; Irwin, N.; Bailey, C.J.; Harriott, P.; Greer, B.; O’Harte, F.P.; Flatt, P.R. J. Endocrinol. 2004, 180, 379-388.

[25] Siegel, E.G.; Gallwitz, B.; Scharf, G.; Mentlein, R.; Morys-Wortmann, C.; Folsch, U.R.; Schrezenmeir, J.; Drescher, K.; Schmidt, W.E. Regul. Peptide. 1999, 79, 93-102.

[26] Sarrauste, D.M.C.; Chavanieu, A.; Grassy, G., Dalle, S.; Salazar, G.; Kervran, A.; Pfeiffer, B.; Renard, P.; Delagrange, P.; Manechez, D.; Bakes, D.; Ktorza, A.; Calas, B. Eur. J. Med. Chem. 2004, 39, 473-480.

[27] Bungo, T.; Shimojo, M.; Masuda, Y.; Saito, N.; Sugahara, K.; Hasegawa, S.; Furuse, M. Life Sci. 1999, 65, PL295-299.

[28] Adelhorst, K.; Hedegaard, B.B.; Knudsen, L.B.; Kirk, O. J. Biol. Chem. 1994, 269, 6275-6278.

[29] Deacon, C.F.; Knudsen, L.B.; Madsen, K.; Wiberg, F.C.; Jacobsen, O.; Holst, J.J. Diabetologia. 1998, 41, 271-278.

[30] Green, B.D.; Gault, V.A.; Mooney, M.H.; Irwin, N.; Bailey, C.J.; Harriott, P.; Greer, B.; Flatt, P.R.; O’Harte, F.P. J. Mol. Endocrinol. 2003, 31, 529-540.

[31] Doyle, M.E.; Greig, N.H.; Holloway, H.W.; Betkey, J.A.; Bernier, M.; Egan, J.M. Endocrinol. 2001, 142, 4462-4468.

[32] Green, B.D.; Mooney, M.H.; Gault, V.A.; Irwin, N.; Bailey, C.J.; Harriott, P.; Greer, B.; Flatt, P.R.; O’Harte, F.P. Metabolism. 2004, 53, 252-259.

[33] Heard, K.R.; Wu, W.; Li, Y.; Zhao, P.; Woznica, I.; Lai, J.H.; Beinborn, M.; Sanford, D.G.; Dimare, M.T.; Chiluwal, A.K.; Peters, D.E.; Whicher, D.; Sudmeier, J.L.; Bachovchin, W.W. J. Med. Chem. 2013, 56, 8339-8351.

[34] Mapelli, C.; Natarajan, S.I.; Meyer, J.P.; Bastos, M.M.; Bernatowicz, M.S.; Lee, V.G.; Pluscec, J.; Riexinger, D.J.; Sieber-McMaster, E.S.; Constantine, K.L.; Smith-Monroy, C.A.; Golla, R.; Ma, Z.; Longhi, D.A.; Shi, D.; Xin, L.; Taylor, J.R.; Koplowitz, B.; Chi, C.L.; Khanna, A.; Robinson, G.W.; Seethala, R.; Antal-Zimanyi, I.A.; Stoffel, R.H.; Han, S.; Whaley, J.M.; Huang, C.S.; Krupinski, J.; Ewing, W.R. J. Med. Chem. 2009, 52, 7788-7799.

[35] Haque, T.S.; Lee, V.G.; Riexinger, D.; Lei, M.; Malmstrom, S.; Xin, L.; Han, S.; Mapelli, C.; Cooper, C.B.; Zhang, G.; Ewing, W.R.; Krupinski, J. Peptides. 2010, 31, 950-955.

[36] Hoang, H.N.; Song, K.; Hill, T.A.; Derksen, D.R.; Edmonds, D.J.; Kok, W.M.; Limberakis, C.; Liras, S.; Loria, P.M.; Mascitti, V.; Mathiowetz, A.M.; Mitchell, J.M.; Piotrowski, D.W.; Price, D.A.; Stanton, R.V.; Suen, J.Y.; Withka, J.M.; Griffith, D.A.; Fairlie, D.P. J. Med. Chem. 2015, 58, 4080-4085.

[37] Koole, C.; Wootten, D.; Simms, J.; Valant, C.; Sridhar, R.; Woodman, O.L.; Miller, L.J.; Summers, R.J.; Christopoulos, A.; Sexton, P.M. Mol. Pharmacol. 2010, 78, 456-465.

[38] Irwin, N.; Flatt, P.R.; Patterson, S.; Green, B.D. Eur. J. Pharmacol. 2010, 628, 268-273.

[39] Chen, D.; Liao, J.; Li, N.; Zhou, C.; Liu, Q.; Wang, G.; Zhang, R.; Zhang, S.; Lin, L.; Chen, K.; Xie, X.; Nan, F.; Young, A.A.; Wang, M.W. Proc. Natl. Acad. Sci. USA. 2007, 104, 943-948.

[40] Sloop, K.W.; Willard, F.S.; Brenner, M.B.; Ficorilli, J.; Valasek, K.; Showalter, A.D.; Farb, T.B.; Cao, J.X.; Cox, A.L.; Michael, M.D.; Gutierrez, S.S.; Tebbe, M.J.; Coghlan, M.J. Diabetes. 2010, 59, 3099-3107.

[41] Liu, Q.; Li, N.; Yuan, Y.; Lu, H.; Wu, X.; Zhou, C.; He, M.; Su, H.; Zhang, M.; Wang, J.; Wang, B.; Wang, Y.; Ma, D.; Ye, Y.; Weiss, H.C.; Gesing, E.R.; Liao, J.; Wang, M.W. J. Med. Chem. 2012, 55, 250-267.

[42] deGraaf, C.; Rein, C.; Piwnica, D.; Giordanetto, F.; Rognan, D. ChemMedChem. 2011, 6, 2159-2169.

[43] Wootten, D.; Simms, J.; Koole, C.; Woodman, O.L.; Summers, R.J.; Christopoulos, A.; Sexton, P.M. J. Pharmacol. Exp. Ther. 2011, 336, 540-550.

[44] Willard, F.S.; Bueno, A.B.; Sloop, K.W. Exp. Diab. Res. 2012, 2012, 1-9.

[45] Eng, J.; Kleinman, W.A.; Singh, L.; Singh, G.; Raufman, J.P. J. Biol. Chem. 1992, 267, 7402-7405.

[46] Paul, S.K.; Maggs, D.; Klein, K.; Best, J.H. J. Diabetes. 2015, 7, 60-67.

[47] Knudsen, L.B.; Nielsen, P.F.; Huusfeldt, P.O.; Johansen, N.L.; Madsen, K.; Pedersen, F.Z.; Thogersen, H.; Wilken, M.; Agerso, H. J. Med. Chem. 2000, 43, 1664-1669.

[48] Gotfredsen, C.F.; Molck, A.M.; Thorup, I.; Nyborg, N.C.; Salanti, Z.; Knudsen, L.B.; Larsen, M.O. Diabetes. 2014, 63, 2486-2497.

[49] Kapitza, C.; Nosek, L.; Jensen, L.; Hartvig, H.; Jensen, C.B.; Flint, A. J. Clin. Pharmacol. 2015, 55, 497-504.

[50] Matthews, J.E.; Stewart, M.W.; De Boever, E.H.; Dobbins, R.L.; Hodge, R.J.; Walker, S.E.; Holland, M.C.; Bush, M.A. J. Clin. Endocrinol. Metab. 2008, 93, 4810-4817.

[51] Muscogiuri, G.; Gastaldelli, A. Drugs Today (Barc). 2014, 50, 665-678.

[52] Nauck, M.A.; Ratner, R.E.; Kapitza, C.; Berria, R.; Boldrin, M.; Balena, R. Diabetes Care. 2009, 32, 1237-1243.

[53] Seshasai, S.R.; Bennett, R.L.; Petrie, J.R.; Bengus, M.; Ekman, S.; Dixon, M.; Herz, M.; Buse, J.B.; Ray, K.K. Diabetes Obes. Metab. 2015, 17, 505-510.

[54] Johnson, L.M.; Barrick, S.; Hager, M.V.; McFedries, A.; Homan, E.A.; Rabaglia, M.E.; Keller, M.P.; Attie, A.D.; Saghatelian, A.; Bisello, A.; Gellman, S.H. J. Am. Chem. Soc. 2014, 136, 12848-12851.

[55] Cheloha, R.W.; Maeda, A.; Dean, T.; Gardella, T.J.; Gellman, S.H. Nat. Biotechnol. 2014, 32, 653-655.

[56] Lorenz, M.; Evers, A.; Wagner, M. Bioorg. Med. Chem. Lett. 2013, 23, 4011-4018.

[57] Gao, M.; Tian, H.; Ma, C.; Gao, X.; Guo, W.; Yao, W. Appl. Biochem. Biotech. 2010, 162, 155-165.

[58] Ueda, T.; Tomita, K.; Notsu, Y.; Ito, T.; Fumoto, M.; Takakura, T.; Nagatome, H.; Takimoto, A.; Mihara, S.; Togame, H.; Kawamoto, K.; Iwasaki, T.; Asakura, K.; Oshima, T.; Hanasaki, K.; Nishimura, S.; Kondo, H. J. Am. Chem. Soc. 2009, 131, 6237-6245.