Since the invention of solid phase synthetic methods by Merrifield in 1963, the\r\nnumber of research groups focusing on peptide synthesis has grown exponentially.\r\nHowever, the original step-by-step synthesis had limitations: the purity of the final product\r\ndecreased with the number of coupling steps. After the development of Boc and Fmoc\r\nprotecting groups, novel amino acid protecting groups and new techniques were introduced\r\nto provide high quality and quantity peptide products. Fragment condensation was a\r\npopular method for peptide production in the 1980s, but unfortunately the rate of\r\nracemization and reaction difficulties proved less than ideal. Kent and co-workers\r\nrevolutionized peptide coupling by introducing the chemoselective reaction of unprotected\r\npeptides, called native chemical ligation. Subsequently, research has focused on the\r\ndevelopment of novel ligating techniques including the famous click reaction, ligation of\r\npeptide hydrazides, and the recently reported -ketoacid-hydroxylamine ligations with 5-\r\noxaproline. Several companies have been formed all over the world to prepare high quality\r\nGood Manufacturing Practice peptide products on a multi-kilogram scale. This review\r\ndescribes the advances in peptide chemistry including the variety of synthetic peptide\r\nmethods currently available and the broad application of peptides in medicinal chemistry.
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