AAC  >> Vol. 6 No. 3 (August 2016)

    Review on Analysis of Related Structure Impurities in Synthetic Peptide Medicines

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陈松辉,陈 妍:国家精细化学品质量监督检验中心,泰州市产品质量监督检验所,江苏 泰州 ;
李 明,李红梅:中国计量科学研究院,化学计量与分析科学研究所,北京

多肽药物杂质质量控制质谱综述Peptide Medicine Impurity Quality Control Mass Spectrometry Review



Peptide medicines have been widely used because of the advantages of relatively low cost, high biological activity, low side effects, target specificity, etc. At present, the peptide drug market is growing twice as fast as other drug markets. Currently, most of the peptides are manufactured by solid-phase peptide synthesis. During synthesis and transportation process, related structure im-purities such as amino acid deletion, amino acid insertion, incomplete removal of protecting groups, oxidation/reduction are easily generated. Many related structure impurities don’t have therapeutic effect; on the contrary they have toxic and side effect. In the paper, the analysis of related structure impurities in synthetic peptide medicines is systematically reviewed. This will be helpful to establish related regulation on quality control of medicine and improve quality of peptide medicine.

陈松辉, 李明, 李红梅, 陈妍. 合成多肽药物中相关结构杂质分析综述[J]. 分析化学进展, 2016, 6(3): 43-50. http://dx.doi.org/10.12677/AAC.2016.63007


[1] Sun, J., Chen, X., Deng, C., et al. (2007) Direct Formation of Giant Vesicles from Synthetic Polypeptides. Langmuir, 23, 8308-8315. http://dx.doi.org/10.1021/la701038f
[2] Nestor Jr., J.J. (2009) The Medicinal Chemistry of Peptides. Current Medicinal Chemistry, 16, 99-4418. http://dx.doi.org/10.2174/092986709789712907
[3] Vlieghe, P., Lisowski, V., Martinez, J., et al. (2010) Synthetic the Rapeutic Peptides: Science and Market. Drug Discovery Today, 15, 40-56. http://dx.doi.org/10.1016/j.drudis.2009.10.009
[4] Craik, D.J., Fairlie, D.P., Liras, S., et al. (2013) The Future of Peptide Based Drugs. Chemical Biology & Drug Design, 81, 136-147. http://dx.doi.org/10.1111/cbdd.12055
[5] Merrifield, R.B. (1963) Solid Phase Peptide Synthesis I: The Synthesis of a Tetrapeptide. Journal of the American Chemical Society, 85, 2149-2154. http://dx.doi.org/10.1021/ja00897a025
[6] Tamura, K. and Alexander, R.W. (2004) Peptide Synthesis through Evolution. Cellular and Molecular Life Sciences, 61, 1317-1330. http://dx.doi.org/10.1007/s00018-004-3449-9
[7] Amblard, M., Fehrentz, J.A., Martinez, J., et al. (2006) Methods and Protocols of Modern Solid Phase Peptide Synthesis. Molecular Biotechnology, 33, 236-254. http://dx.doi.org/10.1385/MB:33:3:239
[8] Isidro-Llobet, A., Alvarez, M. and Albericio, F. (2009) Amino Acid-Protecting Groups. Chemical Reviews, 109, 2455- 2504. http://dx.doi.org/10.1021/cr800323s
[9] Santagada, V., Frecentese, F., Perissutti, E., et al. (2009) Microwave Assisted Synthesis: A New Technology in Drug Discovery. Mini-Reviews in Medicinal Chemistry, 9, 340-358. http://dx.doi.org/10.2174/1389557510909030340
[10] Bacsa, B., Desai, B., Dibo, G., et al. (2006) Rapid Solid-Phase Peptide Syn-thesis Using Thermal and Controlled Microwave Irradiation. Journal of Peptide Science, 12, 633-638. http://dx.doi.org/10.1002/psc.771
[11] D’Hondt, M., Bracke, N., Taevernier, L., et al. (2014) Related Impurities in Peptide Medicines. Journal of Pharmaceutical and Biomedical Analysis, 101, 2-30. http://dx.doi.org/10.1016/j.jpba.2014.06.012
[12] Marder, O. and Albericio, F. (2003) Industrial Application of Coupling Reagents in Peptides. Chimica Oggi, 6, 35-40.
[13] Sanz-Nebot, V., Benavente, F., Toro, I., et al. (2004) Separation and Characterization of Complex Crude Mixtures Produced in the Synthesis of Therapeutic Peptide Hormones by Liquid Chromatography Coupled to Electrospray Mass Spectrometry (LC-ES-MS). Analytica Chimica Acta, 521, 25-36. http://dx.doi.org/10.1016/j.aca.2004.05.041
[14] Sanz-Nebot, V., Benavente, F., Toro, I., et al. (2003) Liquid Chromatography-Mass Spectrometry Approach for the Characterisation and Purification of Crude Synthetic Peptide Hormones. Analytical and Bioanalytical Chemistry, 377, 306-315. http://dx.doi.org/10.1007/s00216-003-2104-x
[15] Sanz-Nebot, V., Benavente, F., Toro, I., et al. (2002) Liquid Chromatography Mass Spectrometry and Capillary Electrophoresis Combined Approach for Separation and Characterization of Multicomponent Peptide Mixtures Applications to Crude Products of Leuprolide Synthesis. Journal of Chromatography A, 950, 99-111. http://dx.doi.org/10.1016/S0021-9673(02)00025-0
[16] Sanz-Nebot, V., Benavente, F., Castillo, A. and Barbosa, J. (2000) Liquid Chromatography-Electrospray Mass Spectrometry of Multicomponent Peptide Mixtures, Characterization of a Mixture from the Synthesis of the Hormone Goserelin. Journal of Chromatography A, 889, 119-133. http://dx.doi.org/10.1016/S0021-9673(00)00394-0
[17] Sanz-Nebot, V., Benavente, F. and Barbosa, J. (2000) Separation and Char-acterization of Multicomponent Peptide Mixtures by Liquid Chromatography Electrospray Ionization Mass Spectrometry, Applications to Crude Products of the Synthesis of Leuprolide. Journal of Chromatography A, 870, 315-334. http://dx.doi.org/10.1016/S0021-9673(99)01088-2
[18] Sanz-Nebot, V., Toro, I., Garcés, A. and Barbosa, J. (1999) Separation and Identification of Peptide Mixtures in a Synthesis Crude of Carbetocin by Liquid Chromatography-Electrospray Ionization Mass Spectrometry. Rapid Communications in Mass Spectrometry, 13, 2341-2347. http://dx.doi.org/10.1002/(SICI)1097-0231(19991215)13:23<2341::AID-RCM795>3.0.CO;2-9
[19] Sanz-Nebot, V., Toro, I., Cas-tillo, A. and Barbosa, J. (2001) Investigation of Synthetic Peptide Hormones by Liquid Chromatography Coupled to Pneumatically Assisted Electrospray Ionization Mass Spectrometry: Analysis of a Synthesis Crude of Peptide Triptorelin. Rapid Communications in Mass Spectrometry, 15, 1031-1039. http://dx.doi.org/10.1002/rcm.343
[20] Taichrib, A., Scriba, G.K.E. and Neusü, C. (2011) Identification and Characterization of Impurities of Tetracosactide by Capillary Electrophoresis and Liquid Chromatography Coupled to Time-of-Flight Mass Spectrometry. Analytical and Bioanalytical Chemistry, 401, 1365-1375. http://dx.doi.org/10.1007/s00216-011-5183-0
[21] De Spiegeleer, B., Vergote, V., Pezeshki, A., Peremans, K. and Burvenich, C. (2008) Impurity Profiling Quality Control Testing of Synthetic Peptides Using Liquid Chromatography-Photodiode Array-Fluorescence and Liquid Chromatography-Electrospray Ionization-Mass Spec-trometry: The Obestatin Case. Analytical Biochemistry, 376, 229-234. http://dx.doi.org/10.1016/j.ab.2008.02.014
[22] Verbeke, F., Wynendaele, E., Braet, S., D’Hondt, M. and De Spiegeleer, B. (2015) Quality Evaluation of Synthetic Quorum Sensing Peptides Used in R&D. Journal of Pharmaceutical Analysis, 5, 169-181. http://dx.doi.org/10.1016/j.jpha.2014.12.002
[23] Isidro-Llobet, A., Just-Baringo, X., Ewenson, A., Álvarez, M. and Albericio, F. (2007) Fmoc-2-mercaptobenzothiazole, for the Introduction of the Fmoc Moiety Free of Side-Reactions. Peptide Science, 88, 733-737. http://dx.doi.org/10.1002/bip.20732
[24] Ji, J.A., Zhang, B., Cheng, W. and John Wang, Y. (2009) Methionine, Tryptophan, and Histidine Oxidation in a Model Protein, PTH: Mechanisms and Stabilization. Journal of Pharmaceutical Sciences, 98, 4485-4500. http://dx.doi.org/10.1002/jps.21746
[25] Uchida, K. (2003) Histidine and Lysine as Targets of Oxidative Modification. Amino Acids, 25, 249-257. http://dx.doi.org/10.1007/s00726-003-0015-y
[26] Dalle-Donne, I., Rossi, R., Giustarini, D., Milzani, A. and Colombo, R. (2003) Protein Carbonyl Groups as Biomarkers of Oxidative Stress. Clinica Chimica Acta, 329, 23-38. http://dx.doi.org/10.1016/S0009-8981(03)00003-2
[27] Palasek, S.A., Cox, Z.J. and Collins, J.M. (2007) Limiting Racemization and Aspartimide Formation in Micro-Wave Enhanced Fmoc Solid Phase Peptide Synthesis. Journal of Peptide Science, 13, 143-148. http://dx.doi.org/10.1002/psc.804
[28] Loffrendo, C., Assuncão, N.A., Gerhardt, J. and Miranda, M.T.M. (2009) Microwave Assisted Solid-Phase Peptide Synthesis at 60˚C: Alternative Conditions with Low Enantiomerization. Journal of Peptide Science, 15, 808-817. http://dx.doi.org/10.1002/psc.1178
[29] Souza, M.P., Tavares, M.F.M. and Miranda, M.T.M. (2004) Racemization in Stepwise Sol-id-Phase Peptide Synthesis at Elevated Temperatures. Tetrahedron, 60, 4671-4681. http://dx.doi.org/10.1016/j.tet.2004.03.070
[30] Han, Y., Albericio, F. and Barany, G. (1997) Occurrence and Minimization of Cys-teine Racemization during Stepwise Solid-Phase Peptide Synthesis. The Journal of Organic Chemistry, 62, 4307-4312. http://dx.doi.org/10.1021/jo9622744
[31] Angell, Y., Alsina, J., Albericio, F. and Barany, G. (2002) Practical Protocols for Stepwise Solid-Phase Synthesis of Cysteine-Containing Peptides. The Journal of Peptide Research, 60, 292-299. http://dx.doi.org/10.1034/j.1399-3011.2002.02838.x
[32] Kaiser, T., Nicholson, G., Kohlbau, H. and Voelter, W. (1996) Racemization Studies of Fmoc-Cys(Trt)-OH during Stepwise Fmoc-Solid Phase Peptide Synthesis. Tetrahedron Letters, 37, 1187-1190. http://dx.doi.org/10.1016/0040-4039(95)02406-9
[33] Elsawy, M.A., Hewage, C. and Walker, B. (2012) Racemization of N-Fmoc Phenylglycine under Mild Microwave- SPPS and Conventional Stepwise SPPS Conditions: Attempts to Develop Strategies for Overcoming This. Journal of Peptide Science, 18, 302-311. http://dx.doi.org/10.1002/psc.2398
[34] Montalbetti, C.A.G.N. and Falque, V. (2005) Amide Bond Formation and Peptide Coupling. Tetrahedron, 61, 10827- 10852. http://dx.doi.org/10.1016/j.tet.2005.08.031
[35] Finder, V.H., Vodopivec, I., Nitsch, R.M. and Glockshuber, R. (2010) The Recom-binant Amyloid-β Peptide Aβ1-42 Aggregates Faster and Is More Neurotoxic than Synthetic Aβ1-42. Journal of Molecular Biology, 396, 9-18. http://dx.doi.org/10.1016/j.jmb.2009.12.016
[36] Lai, M.C. and Topp, E.M. (1999) Solid-State Chemical Stability of Proteins and Peptides. Journal of Pharmaceutical Sciences, 88, 489-500. http://dx.doi.org/10.1021/js980374e
[37] Kinumi, T., Goto, M., Eyama, S., Kato, M., Kasama, T. and Takatsu, A. (2012) Development of SI-Traceable C-Pep- tide Certified Reference Material NMIJ CRM 6901-a Using Isotope-Dilution Mass Spectrometry-Based Amino Acid Analyses. Analytical and Bioanalytical Chemistry, 404, 13-21. http://dx.doi.org/10.1007/s00216-012-6097-1
[38] Litowski, J.R., Semchuk, P.D., Mant, C.T. and Hodges, R.S. (1999) Hydrophilic Interaction/Cation-Exchange Chromatography for the Purification of Synthetic Peptides from Closely Related Impurities: Serine Side-Chain Acetylated Peptides. The Journal of Peptide Research, 54, 1-11. http://dx.doi.org/10.1034/j.1399-3011.1999.00066.x
[39] Cromwell, M.E.M., Hilario, E. and Jacobson, F. (2006) Protein Aggregation and Bioprocessing. The AAPS Journal, 8, E572-E579. http://dx.doi.org/10.1208/aapsj080366
[40] Liu, S., Zhou, L., Chen, L., et al. (2008) Effect of Structural Parameters of Peptides on Dimer Formation and Highly Oxidized Side Products in the Oxidation of Thiols of Linear Analogues of Human β-Defensin 3 by DMSO. Journal of Peptide Science, 15, 95-106. http://dx.doi.org/10.1002/psc.1100