Isoacyl Dipeptides

Isoacyl dipeptides are used to prepare depsipeptides in which the peptide chain is attached to the side chain oxygen atom of serine or threonine residues instead of the alpha nitrogen. Depsipeptides are less prone to aggregation than their standard peptide analogs because the structure of depsipeptides disrupts inter chain hydrogen bonding responsible for aggregation. Isoacyl dipeptides are used to prepare depsipeptides in which the peptide chain is attached to the side chain oxygen atom of serine or threonine residues instead of the alpha nitrogen atom.  Depsipeptides are less prone to aggregation than their standard peptide analogs because the structure of depsipeptides disrupts inter chain hydrogen bonding responsible for aggregation.  This also improves the solubility of depsipeptides compared to the standard analogs.  The depsipeptides are stable under acidic conditions and can be purified by HPLC.  When the pH is adjusted to 7.4 or greater, depsipeptides undergo O->N acyl shift to form the native peptide.  As HPLC purification of peptides is normally performed under acidic conditions, this provides an efficient way to avoid solubility problems when purifying difficult peptides.

Isoacyl dipeptides can be formed on solid phase resins, but acylating amino acid is subject to racemization.  When the reaction is performed in solution, however, the extent of racemization is negligible.  Therefore, preformed isoacyl dipeptides are utilized to incorporate the O-acyl unit.

Isoacyl dipeptides are useful building blocks for assembling large peptides and small proteins by segment condensation.  In addition to improving the solubility of peptides segments, isoacyl dipeptides have other benefits.  Unlike regular peptides, peptides containing an isoacyl dipeptide at the C-terminus can be coupled to other peptide segments with little racemization of the C-terminal amino acid.  By designing the peptide segments with isoacyl dipeptides at the C-terminals, large peptides or small proteins can be efficiently prepared in high diastereomeric purity.

Tips for Utilizing Isoacyl Dipeptides

Isoacyl dipeptides are most effective when they are utilized at the beginning of a hydrophobic segment of the peptide.  In addition, isoacyl dipeptides are most effective when they are positioned with at least six amino acid residues between the isoacyl dipeptide and other aggregation disrupting units such as proline residues, pseudoproline, and amino acids with Hmb or Dmb protection.  The isoacyl dipeptide should also be at least six amino acid residues from the C-terminal.

Isoacyl dipeptides have been used in a synthesis of human insulin.

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