Abstract
Peptide drug development has made significant progress over the last century. The discovery of solid-phase peptide synthesis has enabled chemists to synthesize various peptides with divergent sequence patterns. However, due to the increased demand for various peptide sequences in the modern pharmaceutical industry, there is always room for new methods to modify the existing methods to improve yield, purity, and synthesis time. The current century has witnessed a lot of progress in the field of peptide synthesis, including developments in new synthetic strategies, suitable selection of protecting groups, and introduction of efficient coupling reagents, as well as the development of automated peptide synthesizers. This chapter will give a summary of the recent reports on the most significant breakthroughs in peptide chemical synthesis in current years.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Anderson GW (1960) New approaches to peptide synthesis. Ann N Y Acad Sci 88:676–688
Angell YM, García-Echeverría C, Rich DH (1994) Comparative studies of the coupling of N-methylated, sterically hindered amino acids during solid-phase peptide synthesis. Tetrahedron Lett 35:5981–5984
Babu VVS, Rao RVR (2005) Microwave irradiated high-speed solution synthesis of peptide acids employing Fmoc-amino acid pentafluorophenyl esters as coupling agents. Indian J Chem 44B:2328–2332
Bang D, Kent SB (2004) A one-pot total synthesis of crambin. Angew Chem Int Ed 43:2534–2538
Barany G, Albricio F, Biancalana S et al (1992) Biopolymer syntheses on novel polyethylene glycol-polystyrene (PEG-PS) graft supports. Minnesota University Minneapolis Department of Chemistry, Minneapolis, MN
Blanco-Canosa JB, Dawson PE (2008) An efficient Fmoc-SPPS approach for the generation of thioester peptide precursors for use in native chemical ligation. Angew Chem Int Ed 120:6957–6961
Bondalapati S, Jbara M, Brik A (2016) Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins. Nat Chem 8:407–418
Bonnamour J, Métro TX, Martinez J et al (2013) Environmentally benign peptide synthesis using liquid-assisted ball-milling: application to the synthesis of Leu-enkephalin. Green Chem 15:1116–1120
Cabrele C, Martinek TA, Reiser O et al (2014) Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry. J Med Chem 57:9718–9739
Carpino LA (1993) 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J Am Chem Soc 115:4397–4398
Carpino LA, Han GY (1970) 9-Fluorenylmethoxycarbonyl function, a new base-sensitive amino-protecting group. J Am Chem Soc 92:5748–5749
Carpino LA, El-Faham A, Minor CA (1994) Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis. J Chem Soc Chem Comm 2:201–203
Carpino LA, Imazumi H, El-Faham A et al (2002) The uronium/guanidinium peptide coupling reagents: finally, the true uronium salts. Angew Chem Int Ed 41:441–445
Chatterjee J, Gilon C, Hoffman A et al (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41:1331–1342
Chatterjee J, Rechenmacher F, Kessler H (2013) N-methylation of peptides and proteins: an important element for modulating biological functions. Angew Chem Int Ed 52:254–269
Cheloha RW, Watanabe T, Dean T (2016) Backbone modification of a parathyroid hormone receptor-1 antagonist/inverse agonist. ACS Chem Biol 1:2752–2762
Clark RJ, Craik DJ (2010) Invited review native chemical ligation applied to the synthesis and bioengineering of circular peptides and proteins. Peptide Sci 94:414–422
Collins JM, Collins MJ (2003) Biopolymers 71:267
Collins JM, Porter KA, Singh SK et al (2014) High-efficiency solid phase peptide synthesis (HE-SPPS). Org Lett 16:940–943
Coste J, Le-Nguyen D, Castro B (1990) PyBOP®: a new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett 31:205–208
Dawson PE, Muir TW, Clark-Lewis I et al (1994) Synthesis of proteins by native chemical ligation. Science 266:776–779
Declerck V, Nun P, Martinez J et al (2009) Solvent-free synthesis of peptides. Angew Chem Int Ed 48:9318–9321
Diao L, Meibohm B (2013) Pharmacokinetics and pharmacokinetic–pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet 52:855–868
Dirksen A, Dawson PE (2008) Expanding the scope of chemoselective peptide ligations in chemical biology. Curr Opin Chem Biol 12:760–766
Domalaon R, Zhanel GG, Schweizer F (2016) Curr Top Med Chem 16:141–155
El-Faham A, Funosas RS, Prohens R et al (2009) COMU: a safer and more effective replacement for benzotriazole-based uronium coupling reagents. Chem Eur J 15:9404–9416
Erdelyi M, Gogoll A (2002) Rapid microwave-assisted solid phase peptide synthesis. Synthesis 11:1592–1596
Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128
Galanis AS, Albericio F, Grøtli M (2009) Solid-phase peptide synthesis in water using microwave-assisted heating. Org Lett 11:4488–4491
Gibson SE, Lecci C (2006) Amino acid derived macrocycles-an area driven by synthesis or application? Angew Chem Int Ed 45:1364–1377
Gieselman MD, Xie L, Van Der Donk WA (2001) Synthesis of a selenocysteine-containing peptide by native chemical ligation. Org Lett 3:1331–1334
Guzmán F, Barberis S, Illanes A (2007) Peptide synthesis: chemical or enzymatic. Electron J Biotechnol 10:279–314
Haase C, Seitz O (2008) Extending the scope of native chemical peptide coupling. Angew Chem Int Ed 47:1553–1556
Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nature Rev Drug Disc 2:214–221
Hartrampf N, Saebi A, Poskus M et al (2020) Synthesis of proteins by automated flow chemistry. Science 368:980–987
Henninot A, Collins JC, Nuss JM (2018) The current state of peptide drug discovery: back to the future? J Med Chem 61:1382–1414
Hondal RJ, Nilsson BL, Raines RT (2001) Selenocysteine in native chemical ligation and expressed protein ligation. J Am Chem Soc 123:5140–5141
Jad YE, Kumar A, El-Faham A et al (2019) Green transformation of solid-phase peptide synthesis. ACS Sustain Chem Eng 7:3671–3683
Jiang W, Zhang B, Fan C et al (2017) Mirror-image polymerase chain reaction. Cell Discov 3:1–7
Kumar D, Bhalla TC (2005) Microbial proteases in peptide synthesis: approaches and applications. Appl Microbiol Biotechnol 68:726–736
Liu Y, Hu Y, Liu T (2012) Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: medicinal chemistry and preclinical aspects. Curr Med Chem 19:3982–3999
Macmillan D (2006) Evolving strategies for protein synthesis converge on native chemical ligation. Angew Chem Int Ed 45:7668–7672
Mahindra A, Sharma KK, Jain R (2012) Rapid microwave-assisted solution-phase peptide synthesis. Tetrahedron Lett 53:6931–6935
Mahindra A, Nooney K, Uraon S et al (2013) Microwave-assisted solution phase peptide synthesis in neat water. RSC Adv 3:16810–16816
Mahto SK, Howard CJ, Shimko JC (2011) A reversible protection strategy to improve Fmoc-SPPS of peptide thioesters by the N-acylurea approach. Chembiochem 12:2488–2494
Mazmanian SK, Liu G, Ton-That H et al (1999) Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. Science 285:760–763
Merrifield RB (1963) Solid phase peptide synthesis I. the synthesis of a tetrapeptide. J Am Chem Soc 85:2149–2154
Merrifield RB (1985) Solid phase synthesis (Nobel lecture). Angew Chem Int Ed 24:799–810
Merrifield RB (1986) Solid phase synthesis. Science 232:341–347
Mijalis AJ, Thomas DA, Simon MD et al (2017) A fully automated flow-based approach for accelerated peptide synthesis. Nat Chem Biol 13:464–466
Mong SK, Vinogradov AA, Simon MD et al (2014) Rapid total synthesis of DARPin pE59 and barnase. Chembiochem 15:721–733
Mótyán JA, Tóth F, Tőzsér J (2013) Research applications of proteolytic enzymes in molecular biology. Biomol Ther 3:923–942
Murray JK, Gellman SH (2005) Application of microwave irradiation to the synthesis of 14-helical β-peptides. Org Lett 7:1517–1520
Muttenthaler M, Albericio F, Dawson PE (2015) Methods, setup and safe handling for anhydrous hydrogen fluoride cleavage in Boc solid-phase peptide synthesis. Nat Protoc 7:1067–1083
Nguyen GK, Hemu X, Quek JP (2016) Butelase-mediated macrocyclization of d-amino-acid-containing peptides. Angew Chem Int Ed 128:12994–12998
Pedersen SL, Tofteng AP, Malik L (2012) Microwave heating in solid-phase peptide synthesis. Chem Soc Rev 41:1826–1844
Quaderer R, Sewing A, Hilvert D (2001) Selenocysteine-mediated native chemical ligation. Helv Chim Acta 84:1197–1206
Rapp W, Zhang L, Habich R et al (1988) Polystyrene-polyoxyethylene graft copolymers for high-speed peptide synthesis, pp 199–201
Rodríguez H, Suarez M, Albericio F (2010) A convenient microwave-enhanced solid-phase synthesis of short chain N-methyl-rich peptides. J Pept Sci 16:136–140
Sato AK, Viswanathan M, Kent RB et al (2006) Therapeutic peptides: technological advances driving peptides into development. Curr Opin Biotechnol 17:638–642
Schnölzer M, Alewood P, Jones A et al (1992) In situ neutralization in Boc-chemistry solid phase peptide synthesis: rapid, high yield assembly of difficult sequences. Int J Pept Protein Res 40:180–193
Simon MD, Heider PL, Adamo A et al (2014) Rapid flow-based peptide synthesis. Chembiochem 15:713–720
Subirós-Funosas R, Prohens R, Barbas R et al (2009) Oxyma: an efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion. Chem Eur J 15:9394–9403
Torbeev VY, Kent SB (2007) Convergent chemical synthesis and crystal structure of a 203 amino acid “covalent dimer” HIV-1 protease enzyme molecule. Angew Chem Int Ed 46:1667–1670
Tsuda Y, Okada Y (2010) Amino acids, peptides and proteins in organic chemistry. Wiley, Hoboken, NJ, pp 201–251
Uhlig T, Kyprianou T, Martinelli FG (2014) The emergence of peptides in the pharmaceutical business: from exploration to exploitation. EuPA Open Proteom 4:58–69
Ulijn RV, Baragaña B, Halling PJ et al (2002) Protease-catalyzed peptide synthesis on solid support. J Am Chem Soc 124:10988–10989
Ulijn RV, Bisek N, Halling PJ et al (2003) Understanding protease catalysed solid phase peptide synthesis. Org Biomol Chem 1:1277–1281
Våbenø J, Haug BE, Rosenkilde MM (2015) Progress toward rationally designed small-molecule peptide and peptidomimetic CXCR4 antagonists. Future Med Chem 7:1261–1283
Verlander M (2007) Industrial applications of solid-phase peptide synthesis–a status report. Int J Pept Res Ther 13:75–82
Wang L, Wang N, Zhang W et al (2022) Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther 7:48
Werner HM, Cabalteja CC, Horne WS (2016) Peptide backbone composition and protease susceptibility: impact of modification type, position, and tandem substitution. Chembiochem 17:712–718
Wu Z, Guo X, Guo Z (2011) Sortase A-catalyzed peptide cyclization for the synthesis of macrocyclic peptides and glycopeptides. Chem Commun 47:9218–9220
Yan LZ, Dawson PE (2001) Synthesis of peptides and proteins without cysteine residues by native chemical ligation combined with desulfurization. J Am Chem Soc 123:526–533
Zheng JS, Tang S, Huang YC et al (2013) Development of new thioester equivalents for protein chemical synthesis. Acc Chem Res 46:2475–2484
Acknowledgment
G.K.R. is thankful to the National Institute of Pharmaceutical Education and Research, S. A. S. Nagar for providing a Senior Research Fellowship. R.M. thanks the Department of Science and Technology, New Delhi for DST Faculty Inspire Fellowship (No. DST/INSPIRE/04/2020/002499).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Rathod, G.K., Misra, R., Jain, R. (2023). Advances in Peptide Synthesis. In: Singh, P.P. (eds) Recent Advances in Pharmaceutical Innovation and Research. Springer, Singapore. https://doi.org/10.1007/978-981-99-2302-1_8
Download citation
DOI: https://doi.org/10.1007/978-981-99-2302-1_8
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-99-2301-4
Online ISBN: 978-981-99-2302-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)