MINIREVIEW ARTICLE Solid-phase peptide synthesis (SPPS), C-terminal vs. side-chain anchoring: a reality or a myth Prabhakar Cherkupally • Gerardo A. Acosta • Suhas Ramesh • Beatriz G. De la Torre • Thavendran Govender • Hendrik G. Kruger • Fernando Albericio Received: 8 January 2014 / Accepted: 7 April 2014 Ó Springer-Verlag Wien 2014 Abstract Here we review the strategies for the solid- phase synthesis of peptides starting from the side chain of the C-terminal amino acid. Furthermore, we provide experimental data to support that C-terminal and side-chain syntheses give similar results in terms of purity. However, the stability of the two bonds that anchor the peptide to the polymer may determine the overall yield and this should be considered for the large-scale production of peptides. In addition, resins/linkers which do not subject to side reac- tions can be preferred for some peptides. Keywords Solid-phase peptide synthesis Á Stepwise elongation Á Side-chain anchoring Á C-terminal acid peptide The importance of peptides in modern science has grown exponentially in recent years. In addition to that, peptides are considered a firm alternative to small molecules for the treat- ment of a large number of human and animal diseases (Albericio and Kruger 2012; Kaspar and Reichert 2013; Scognamiglio et al. 2013; Gongora-Benitez et al. 2014). The cosmetic and nutraceutical industries are also introducing peptides into their products (Mentel et al. 2012; Udenigwe and Howard 2013). Furthermore, peptides are also used in the development of drug delivery systems and diagnostic kits (Li et al. 2012; Vasconcelos et al. 2013). Finally, new biomaterials for a broad range of applications are currently prepared from peptides (Nune et al. 2013; Menzel 2013). The introduction of these biomolecules into our everyday lives (Zompra et al. 2009; Chandrudu et al. 2013) has unquestionably been fuelled by the development and optimization of the solid-phase syn- thetic strategy, first described by Merrifield (Merrifield 1963). In brief, the solid-phase peptide synthesis (SPPS) is based on the concourse of a supported protecting group—a polymeric support—that facilitates the stepwise elongation of this biopolymer through sequential steps of coupling and deprotection of protected amino acids, thus allowing the use of large excess of reagents. At the end of the synthetic process, a chemical treatment is usually applied to remove the protecting groups and detach the peptide from the resin (Albericio et al. 2011; Gongora-Benitez et al. 2013). All peptides have the following four types of functional groups which can in principle be used for attachment to the polymeric support: (1) C-terminal function (C to N strategy); (2) N-terminal function (N to C strategy); (3) backbone; and (4) side chain (if a trifunctional amino acid is present) (Fig. 1). P. Cherkupally Á S. Ramesh Á B. G. De la Torre Á T. Govender Á H. G. Kruger Á F. Albericio Catalysis and Peptide Research Unit, School of Health Sciences, University of Kwazulu-Natal, Durban 4001, South Africa P. Cherkupally Á G. A. Acosta Á F. Albericio (&) Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain e-mail: albericio@irbbarcelona.org; Albericio@ukzn.ac.za G. A. Acosta Á F. Albericio CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain B. G. De la Torre Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Dr. Aiguader 88, 08003 Barcelona, Spain F. Albericio School of Chemistry and Physics, University of Kwazulu-Natal, Durban 4001, South Africa F. Albericio Department of Organic Chemistry, University of Barcelona, Martı ´ i Franque ´s 1-11, 08028 Barcelona, Spain 123 Amino Acids DOI 10.1007/s00726-014-1746-7