Depsipeptide

A depsipeptide is a peptide in which one or more amide, -C(O)NHR-, linkages are replaced by the corresponding ester, -C(O)OR-.^[1] Many depsipeptides have both peptide and ester linkages.^[2] Elimination of the N–H group in a peptide structure results in a decrease of H-bonding capability, which is responsible for secondary structure and folding patterns of peptides, thus inducing structural deformation of the helix and β-sheet structures.^[2][3] Because of decreased resonance delocalization in esters relative to amides, depsipeptides have lower rotational barriers for cis-trans isomerization and therefore they have more flexible structures than their native analogs.^[2][3] They are mainly produced in nature by soil and marine sediment inhabiting bacteria.^[4]

An example of a depsipeptide drug is the anticancer agent romidepsin, a known histone deacetylase inhibitor (HDACi). It was first isolated as a fermentation product from the soil bacterium Chromobacterium violaceum by the Fujisawa Pharmaceutical Company.^[5][6]

Streptogramins, specifically streptogramin B antibiotics, are depsipeptides that bind to the 50S subunit of bacterial ribosomes.^[7] Etamycin was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model.^[8]

Several depsipeptides from Streptomyces exhibit antimicrobial activity.^[9][10] 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.^[11][12][13]

Depsipeptides can be formed through a Passerini reaction.^[14]