Method for the site-specific modification of peptide alpha amines
AssigneeThe Regents of the University of California
InventorsStephen Miller, Thomas S. Scanlan
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Abstract
A peptide comprising a free terminal alpha amine is treated with an aryl sulfonamide activating agent, resulting in an activated amide. The resulting activated amide is deprotonated with a base and modified by the addition of a substituent group. The aryl sulfonamide activating group is cleaved using a nucleophilic substitution reaction. The method is particularly useful for the modification of peptides at specific N-alpha positions, and is compatible with conventional solid phase peptide synthesis, including those that utilize Fmoc protecting groups.
Claims17
A method of modifying a peptidic substrate attached to a solid support, wherein said peptidic substrate comprises a terminal primary alpha amine to generate a secondary amine the method comprising:
- treating said peptidic substrate attached to a solid support with an aryl sulfonyl activating agent that, on reaction with said primary amine, results in an activated sulfonamide;
- and
- deprotonating said activated sulfonamide with a base having a pKa in the range of about 12 to 15 and selectively modifying the resulting deprotonated amide with a modifying agent to provide a substituted amide;
- cleaving the activating group from said substituted amide to provide a substituted, secondary amine.
The method for introducing an N-alpha substituent at a specific site in a polypeptide during solid phase peptide synthesis, the method comprising:
- synthesizing a polypeptide by stepwise addition of amino acids or analogs thereof while bound to a solid phase until the target residue has been added and deprotected to provide a free primary amine at an alpha position;
- activating the alpha nitrogen by addition of an aryl sulfonyl activating agent that converts said primary amine to an activated sulfonamide;
- deprotonating said activated sulfonamide with base having a pKa in the range from about 12 to 15 and selectively modifying the resulting deprotonated sulfonamide with a modifying agent to provide a substituted sulfonamide;
- cleaving the aryl sulfonyl activating group from said substituted sulfonamide to provide a substituted, secondary amine;
- and
- continuing the stepwise addition of amino acids or analogs thereof to said polypeptide.
A method of synthesizing a library of compounds, the method comprising:
- providing a library of peptidic substrates attached to a solid support, each of which comprises a terminal primary alpha amine group;
- treating said library of peptidic substrates by addition of an ary sulfonyl activating agent that converts said primary amines to activated sulfonamides;
- deprotonating said activated sulfonamides with base having a pKa in a range from about 12 to 15 and selectively modifying the resulting deprotonated sulfonamides with a modifying agent to provide substituted sulfonamides;
- and
- cleaving the aryl sulfonyl activating group from said substituted sulfonamides.
Dependencies are inferred from the claim text.