Depsipeptide

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-.^[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 found in marine and microbial natural products.^[4]

Example of a depsipeptide with 3 amide groups (highlighted blue) and one ester group (highlighted green). R¹ and R³ are organic groups (e. g. methyl) or a hydrogen atom found in α-hydroxycarboxylic acids. R², R⁴ and R⁵ are organic groups or a hydrogen atom found in common amino acids.

Depsipeptide natural products

Enterochelin is a depsipeptide that is an iron-transporter.^[5]

Several depsipeptides have been found to exhibit anti-cancer properties.^[6]

A depsipeptide enzyme inhibitor includes 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.^[7]

Streptogramins, specifically streptogramin B antibiotics, are depsipeptides that bind to the 50S subunit of bacterial ribosomes.^[8] Etamycin was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model.^[9]

Several depsipeptides from Streptomyces exhibit antimicrobial activity.^[10][11] 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.^[12][13][14]

Depsipeptides can be formed through a Passerini reaction.^[15]