A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides |
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| Authors: | Nitin A Patil Dr Julien Tailhades Dr John A Karas Prof Frances Separovic Prof John D Wade Dr Mohammed Akhter Hossain |
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| Institution: | 1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia;2. School of Chemistry, University of Melbourne, Melbourne, VIC, Australia;3. Bio21 Institute, University of Melbourne, Australia |
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| 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. |
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| Keywords: | conjugation heterodimeric peptides N-terminal linkers peptides solid-phase synthesis |
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