Overview of solid phase synthesis of "difficult peptide" sequences

Solid-phase peptide synthesis has contributed immeasurably to the understanding of the chemistry and biology of peptides by enabling their ready preparation in small quantities up to the ton scale. The advantages of the technology, including its simplicity, ease of operation, and general efficiency have far outweighed its limitations. However, despite the general effectiveness of the solid phase synthesis methodology, some peptides are resistant to efficient assembly and are known as "difficult peptides." Such sequences can present serious challenges to the peptide researcher and have been the subject of considerable investigation. This phenomenon is described together with modern approaches designed to minimize or overcome this hitherto long-standing and vexing problem.