10.1021/ja9836287.s001 Lynne E. Canne Lynne E. Canne Paolo Botti Paolo Botti Reyna J. Simon Reyna J. Simon Yijun Chen Yijun Chen Edward A. Dennis Edward A. Dennis Stephen B. H. Kent Stephen B. H. Kent Chemical Protein Synthesis by Solid Phase Ligation of Unprotected Peptide Segments American Chemical Society 1999 group V secretory phospholipase MIF chemical protein synthesis 6 disulfide bonds chemical Protein Synthesis acid Unprotected Peptide Segments polymer support SPCL phase protein synthesis method peptide segments ligation target polypeptide chains target polypeptide chain Solid Phase Ligation 1999-09-09 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Chemical_Protein_Synthesis_by_Solid_Phase_Ligation_of_Unprotected_Peptide_Segments/3673146 In this paper we describe “solid phase chemical ligation” (SPCL), the application of the principles of polymer-supported organic synthesis to the construction of large polypeptide chains for the total chemical synthesis of proteins. In this method, each building block used is an <i>unprotected</i> peptide segment of 20 or more amino acids. These are consecutively reacted by chemical ligation, the chemoselective reaction of the unprotected peptide segments from aqueous solution, to make the polymer-supported target polypeptide. In a final step, the assembled full-length target polypeptide is released from the aqueous-compatible polymer support. Here we report chemistries for the attachment of the first segment to a polymer support, and for the assembly of the target polypeptide chain starting from the polymer-bound peptide segment. In this solid phase protein synthesis method, large target polypeptide chains can be built efficiently and rapidly by SPCL and, after release from the polymer support, folded to give functional protein molecules. Several examples of the application of SPCL are given:  model peptides consisting of 27 and 68 amino acids, and polypeptides corresponding to the proteins C5a (74 amino acids) and MIF (115 amino acids), were each made in good yield and purity from the consecutive solid phase ligation of peptide segments. In addition, we report the total synthesis by SPCL of the enzyme “human group V secretory phospholipase A<sub>2</sub>” (GV-PLA<sub>2</sub>), which comprises a polypeptide of 118 amino acids containing 6 disulfide bonds. As demonstrated by these examples, SPCL is an important extension of our capabilities for total chemical protein synthesis.