Analytical Techniques: G. Grant, M. Crankshaw, and J. Smith, Amino Acid Analysis. Mant, L. Kondejewski, P. Cachia, O. Monera, and R. Sanchez and A. Smith, Capillary Electrophoresis. Beranova-Giorgianni and D. Burdick and J. Moore, Laser Desorption. Specialized Applications: T. Muir, P. Dawson, M. Fitzgerald, and S. Lauer and G. Yu, T. Pakalns, Y. Dori, J. McCarthy, M. Tirrell, and G. Barbar, C. Woodward, and G. Tam and J. Spetzler, Multiple Antigen Peptide System.
Wade and G. Tregear, Relaxin. Angeletti, L. While these approaches enable to circumvent the use of toxic solvents and bases  , no comparison between ball-milling and conventional approaches was performed, discussed and communicated. Thus, the coupling steps were realized by ball-milling the amino ester salts p-toluenesulfonate or hydrochloride with Boc-AA-OH 1. Of note, it was observed previously under similar reaction conditions that the absence of EtOAc as liquid grinding assistant neat grinding could lead to inhomogeneity of the reagents distribution inside the ball-mill, thereby leading to a lower overall conversion .
Alternatively, removal of the Boc group under mechanochemical conditions was realized. Jump to Scheme 2 Synthesis on solid support For the strategy involving a solid support, the chemistry was slightly different from the one used for BM or in solution, as the standard Fmoc chemistry commonly utilized in laboratories was employed [25,26].
The synthesis was conducted on an Fmoc-A-Wang resin on a 0. Before lyophilization, the peptide was precipitated by the addition of Et2O. Jump to Scheme 3 Comparison of the three different strategies Having these results in hands, a comparison of the three strategies was realised.
Although one could point out that differences could arise from these chemical divergences, the global aim of this study was to establish a comparison based on a practical point of view. Thus, the comparison was based on the isolated yield and purity of intermediates and the final products, on the reaction time, and on the environmental impact. Comparison based on the yields and purities of intermediates and final products Contrary to SPPS where the peptide of interest is isolated at the very end of the process, syntheses performed by BM and in solution allows for a step by step comparison.
Table 1: Yields and purities for the three strategies for each entry, the best result is indicated in bold.
Bechtold, Vanderlei G.
Elofsson, and L. After synthesis completion, peptides are individually cleaved from the polymer support . Modifying the peptide backbone promises a more systematic approach to peptide solubility.
Rodal, Bing Xu.
They will have to be used, if peptides are modified additionally and they are cleaved under specific conditions as, e.
Songster and G. Here, we highlight the importance of automated solid-phase peptide synthesis SPPS in the process of peptide modification. In this study, the challenging VVIA tetrapeptide was synthesized by ball-milling, in solution, and on solid support. Application of automated SPPS for drug development The described method of chemical synthesis of peptides on the solid phase and particularly, its outstanding potential for automation, have led to routine methods in the development of novel pharmaceuticals. Nevertheless, their ability to pass through membranes and the urgent need of alternative, more comfortable administration routes as the commonly used parenteral subcutaneous, intramuscular and intravenous application, have prompted further research in this field .
Journal of the American Chemical Society , 33 ,
Modifying the peptide backbone promises a more systematic approach to peptide solubility.
Elofsson, and L. Rafaela I. Peptide libraries can be created by directed parallel synthesis or complex peptide mixtures and identified by iterative processes or position screenings . The appropriate procedure strongly depends on the application lead-structure discovery, biological investigations, potential drug candidate of the desired peptide. Moya, Marcelo H.
These two strategies are based on substantially different mechanisms, which can lead to a remarkable increase of the potential utility of peptides as pharmaceuticals. Love, W.
Activation and coupling reagents: In order to form peptide bonds by SPPS, the free carboxy terminus has to be transformed into an active, more electrophilic species. Kondejewski, P. Thus, the extended action was proposed to be facilitated by serum albumin binding, which leads to gradual peptide release and an prolonged circulation time . In , a lipidated analog of PP pancreatic polypeptide , a gut hormone that is known to mediate satiety, was developed. Basically, every amino acid containing chemically reactive side chains has to be equipped with a protecting group during peptide assembly by SPPS in order to prevent side reactions and the formation of byproducts. It showed an improved bioavailability demonstrated in a prolonged action in decreasing food intake in mice .