Chemical Synthesis of Human Insulin-Like Peptide-6.
Human insulin-like peptide-6 (INSL-6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL-6 utilizing fluorenylmethyloxycarbonyl-based (Fmoc) solid-phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation-sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine-mediated S-acetamidomethyl (Acm) deprotection and the second utilized iodine-free, sulfoxide-directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL-6 and will further improve synthetic access to other multiple-disulfide-containing peptides with oxidation-sensitive residues.
Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA.
Fangzhou
F
Wu
Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA.
John P
JP
Mayer
Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA.
Alexander N
AN
Zaykov
Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA.
Fa
F
Zhang
Novo Nordisk Research Center Indianapolis, 5225 Exploration Drive, Indianapolis, Indiana, 46241, USA. falx@novonordisk.com.
Fa
F
Liu
Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA. rdimarch@indiana.edu.
Richard D
RD
DiMarchi
D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D007328:Insulin / Q000138:chemical synthesis* / Q000737:chemistry*; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry* / Q000378:metabolism
D004220:Disulfides; D007328:Insulin; D010455:Peptides; D014364:Tryptophan
chemical synthesis; insulin-like peptides; insulin-super family; peptides; proteins