Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 47, Pages 14552-14556Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201604733
Keywords
conjugation; heterodimeric peptides; N-terminal linkers; peptides; solid-phase synthesis
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Funding
- NHMRC (Australia) [1023321]
- ARC Linkage grant [LP120100654]
- Melbourne Research scholarship
- Albert Shimmins Writing-Up Award
- Linkage grant project
- Florey Foundation
- Victorian Government's Operational Infrastructure Support Program
- Australian Research Council [LP120100654] Funding Source: Australian Research Council
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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.
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