Peptide synthesis solid phase, disadvantage

The major disadvantage of solid-phase peptide synthesis is the fact that ail the by-products attached to the resin can only be removed at the final stages of synthesis. Another problem is the relatively low local concentration of peptide which can be obtained on the polymer, and this limits the turnover of all other educts. Preparation of large quantities (> 1 g) is therefore difficult. Thirdly, the racemization-safe methods for acid activation, e.g. with azides, are too mild (= slow) for solid-phase synthesis. For these reasons the convenient Menifield procedures are quite generally used for syntheses of small peptides, whereas for larger polypeptides many research groups adhere to classic solution methods and purification after each condensation step (F.M. Finn, 1976). 

This peptide synthesis, although hampered by some disadvantages, already featured most of the key elements of solid-phase peptide synthesis that have ultimately led to the development of the powerful synthetic protocols used today. 

The first solid-phase peptide synthesis reported by Merrifield had some disadvantages, which were corrected in later versions of this synthesis. The main improvements were the replacement of benzyloxycarbonyl protective groups by the TFA-labile Boc protection, and the use of TFA-resistant linkers cleavable by HF. 

Synthesis on solid supports was first developed by Merrifield [1] for the assembly of peptides. It has expanded to include many different applications including oligonucleotide, carbohydrate, and small-molecule assembly (see Chapters 11 and 14). The repetitive cycle of steps involved in the solid-phase synthesis of biopolymers can be performed manually using simple laboratory equipment or fully automated with sophisticated instrumentation. This chapter examines typical solid-phase reaction kinetics to identify factors that can improve the efficiency of both manual and automated synthesis. The hardware and software features of automated solid-phase instruments are also discussed. The focus of this discussion is not on particular commercial model synthesizers but on the basic principles of instrument operation. These considerations can assist in the design, purchase, or use of automated equipment for solid-phase synthesis. Most contrasting features have advantages and disadvantages and the proper choice of instrumentation depends on the synthetic needs of the user. 

Solid phase peptide synthesis is the only widely practiced technique of facilitation but several other methods have also been proposed for the rapid construction of long peptide chains. Some of these alternative approaches have certain advantages over solid phase synthesis reactions carried out in solution are not affected by the rate-limiting control of the gel. Also, where isolation of intermediates is possible, these can be analyzed and purified. A major disadvantage, however, common to the various techniques discussed below, is that they are less conducive to mechanization and automation than the Merrifield method. 

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