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Depsipeptide

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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).

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Depsipeptide natural products

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.

Enzyme inhibitors

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.

In antibacterial discovery

Etamycin, described above, was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model. Several depsipeptides natural products from Streptomyces have been studied for their antimicrobial activity. These form a new, potential class of antibiotics known as acyldepsipeptides (ADEPs). ADEPs target and activate the casein lytic protease (ClpP) to initiate uncontrolled peptide and unfolded protein degradation, killing many Gram-positive bacteria. Research is still underway to modify ADEPs in order to construct an antibiotic with greater antimicrobial activity.

In antiviral discovery

Several depsipeptides have been found to inhibit HIV, including papuamide, neamphamide A, callipeltin A, and mirabamides A-D.

Research uses

An early practical, and sustaining use of desipeptides as research tools has been as an alternative type of substrates for families of proteases, in order to broaden the observable range of substrate structures and kinetics. Depsipeptides have also been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics.

References

Depsipeptide Wikipedia


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