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US 12,600,746 B2Granted
Synthetic methods using native chemical ligation in flow
AssigneeThe University of Sydney
InventorsRichard J. Payne, Tim Chisholm
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Abstract
The disclosure relates to the synthesis of amide containing compounds in flow. In particular, the disclosure relates to the synthesis of polypeptides via native chemical ligation in flow. The disclosure also relates to selective desulfurization or deselenization of amide containing compounds comprising a thiol, disulfide, selenol or diselenide functional group respectively, particularly polypeptides.
Claims27
A method of preparing a polypeptide n a continuous flow reaction comprising the step of reacting:
- (i) an ester, with
- (ii) a molecule comprising a terminal amino acid selected from the group consisting of cysteine, cystine, an amino acid comprising a thiol, an amino acid comprising a disulfide, selenocysteine, selenocystine, an amino acid comprising a selenol, and an amino acid comprising a diselenide;
- wherein the ester is a thioester or selenoester;
- and
- wherein the ester reacts with the cysteine, cystine, amino acid comprising a thiol, amino acid comprising a disulfide, selenocysteine, selenocystine, amino acid comprising a selenol, or amino acid comprising a diselenide, of the terminal amino acid of the molecule in a continuous flow reaction,
- thereby preparing a polypeptide compound in a continuous flow reaction;
- wherein the polypeptide is defined by formula (I):
- the ester is defined by formula (II):
- the molecule comprising a terminal amino acid selected from the group consisting of cysteine, an amino acid comprising a thiol, selenocysteine, and an amino acid comprising a selenol is defined by formula (III):
- the molecule comprising a terminal amino acid selected from the group consisting of cystine, an amino acid comprising a disulfide, selenocystine and an amino acid comprising a diselenide is defined by formula (IV):
- wherein:
- Nterm is the N-terminus of the polypeptide;
- Cterm is the C-terminus of the polypeptide;
- AA is an amino acid;
- n is an integer;
- (AA)n represents a polypeptide comprising n number of amino acid monomers;
- DG is a displaceable group selected from a thiolate and a selenoate;
- and
- is a portion of an amino acid residue excluding the alpha-amine and alpha-carboxylate of the amino acid residue;
- wherein the portion of the amino acid residue comprises a thiol, disulfide, selenol or diselenide at the ligation site such that the amino acid residue is selected from the group consisting of cysteine, cystine, an amino acid comprising a thiol, an amino acid comprising a disulfide, selenocysteine, selenocystine, an amino acid comprising a selenol, and an amino acid comprising a diselenide.
17 more elements
Dependencies are inferred from the claim text.