A One-Pot Chemically Cleavable Bis-Linker Tether Strategy for the Synthesis of Heterodimeric Peptides

Nitin A. Patil, Julien Tailhades, John A. Karas, Frances Separovic, John D. Wade, Mohammed Akhter Hossain

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14552-14556
Number of pages5
JournalAngewandte Chemie - International Edition
Volume55
Issue number47
DOIs
Publication statusPublished - 14 Nov 2016
Externally publishedYes

Keywords

  • Conjugation
  • Heterodimeric peptides
  • N-terminal linkers
  • Peptides
  • Solid-phase synthesis

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