Depsipeptides

A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR, or more generally, is a molecule that has both peptide and ester linkages in proximity in the same amino acid-containing small molecule or chain. The ester moiety is generally an easily accomplished synthetic alteration, making depsipeptide tool compounds easy to prepare, e.g. in construction of alternative substrates for proteolytic enzymes. As well, nature has many pathways for production of this structural motif, and so depsipeptide natural products are relatively common, and are being studied in a variety of early preclinical therapeutic discovery contexts, including antiinfectives (toward discover of antibacterials and antivirals).

In addition to being manmade constructs (e.g., used as research tools, see below), depsipeptides are also found in nature. A unique and important example is the L-Lys-D-Ala-D-Lac motif found in a particular class of vancomycin-resistant bacterial cell walls, where the mutation resulting in the amide-to-ester alteration prevents the usual hydrogen bonding network between vancomycin and the wall, undermining this compound's general antibacterial activity. The array of depsipeptide natural products discovered to date is extensive, and many have been tested as entry points into particular areas of therapeutic discovery.

In addition to this and related functions as protease inhibitors, examples of "small molecules" depsipeptide enzyme inhibitors include romidepsin, a member of the bicyclic peptide class, a known histone deacetylase inhibitors (HDACi); it was first isolated as a fermentation product from Chromobacterium violaceum by the Fujisawa Pharmaceutical Company. It is being used in the treatment of some cancers, where it is thought to reactivate silenced genes.Spiruchostatin A is another natural depsipeptide and HDAC inhibitor.

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