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A one-pot chemically cleavable bis-linker tether strategy for the synthesis of heterodimeric peptides
Patil, N. A., Tailhades, J., Karas, J. A., Separovic, F., Wade, J. D., & Hossain, M. A. (2016). A one-pot chemically cleavable bis-linker tether strategy for the synthesis of heterodimeric peptides. Angewandte Chemie-International Edition, 55(47), 14552-14556. https://doi.org/10.1002/anie.201604733
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.
