Why peptide synthesis continues to remain a formidable challenge

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Abstract
Striking advances have been made in the synthesis of biologically active peptides. The synthesis of fully active crystalline bovine ribonuclease A by Yajima and Fujii [(1981) Biopolymers 20, 1855–1863] represents an exciting milestone. The main factors contributing to this success include sequential coupling of many small segments and a sophisticated multistage protocol for the final acidolytic cleavage of all protecting groups. However, syntheses of large peptides and proteins and even of many medium‐sized peptides continue to present formidable challenges. In peptide coupling the challenge is to join large peptide segments efficiently and in good yields. For solid‐phase synthesis the challenge is application of polar supports and alternative Nα‐protection. With protecting groups the challenge is to achieve quantitive cleavage at the end of synthesis. Concerning racemization the challenge is to develop sensitive and rapid procedures for measuring racemization during coupling. For purification the challenge is to improve the existing procedures and to search for novel alternative separation principles.

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