TY - JOUR
T1 - A One-Pot Chemically Cleavable Bis-Linker Tether Strategy for the Synthesis of Heterodimeric Peptides
AU - Patil, Nitin A.
AU - Tailhades, Julien
AU - Karas, John A.
AU - Separovic, Frances
AU - Wade, John D.
AU - Hossain, Mohammed Akhter
PY - 2016/11/14
Y1 - 2016/11/14
N2 - Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have developed a novel chemically cleavable bis-linker tether which allows the convenient assembly of two peptide chains as a single "pro"-peptide on the same solid support. Following the peptide cleavage and post-synthetic modifications, this bis-linker tether can be removed in one-step by chemical means. This method was used to synthesize a drug delivery-cargo conjugate, TAT-PKCi peptide, and a two-disulfide bridged heterodimeric peptide, thionin (7-19)-(24-32R), a thionin analogue. To our knowledge, this is the first report of a one-pot chemically cleavable bis-linker strategy for the facile synthesis of cross-bridged two-chain peptides.
AB - Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have developed a novel chemically cleavable bis-linker tether which allows the convenient assembly of two peptide chains as a single "pro"-peptide on the same solid support. Following the peptide cleavage and post-synthetic modifications, this bis-linker tether can be removed in one-step by chemical means. This method was used to synthesize a drug delivery-cargo conjugate, TAT-PKCi peptide, and a two-disulfide bridged heterodimeric peptide, thionin (7-19)-(24-32R), a thionin analogue. To our knowledge, this is the first report of a one-pot chemically cleavable bis-linker strategy for the facile synthesis of cross-bridged two-chain peptides.
KW - Conjugation
KW - Heterodimeric peptides
KW - N-terminal linkers
KW - Peptides
KW - Solid-phase synthesis
UR - http://www.scopus.com/inward/record.url?scp=84981743154&partnerID=8YFLogxK
U2 - 10.1002/anie.201604733
DO - 10.1002/anie.201604733
M3 - Article
AN - SCOPUS:84981743154
SN - 1433-7851
VL - 55
SP - 14552
EP - 14556
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 47
ER -