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-. Many depsipeptides have both peptide and ester linkages. 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. 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. They are mainly found in marine and microbial natural products.

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.

Several depsipeptides have been found to exhibit anti-cancer properties.

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.

Etamycin was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model. Several depsipeptides from Streptomyces exhibit 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.

Depsipeptides can be formed through a Passerini reaction.

Further reading

• papuamide Ford, PW; Gustafson, KR; McKee, TC; Shigematsu, N; Maurizi, LK; Pannell, LK; Williams, DE; de Silva, ED; Lassota, P; Allen, TM; Van Soest, R; Andersen, RJ; Boyd, MR (1999). "Papuamides A-D, HIV-Inhibitory and Cytotoxic Depsipeptides from the Sponges Theonella mirabilis and Theonella swinhoei Collected in Papua New Guinea". J. Am. Chem. Soc. 121: 5899–5909. doi:10.1021/ja990582o.
• neamphamide A Oku, N; Gustafson, KR; Cartner, LK; Wilson, JA; Shigematsu, N; Hess, S; Pannell, LK; Boyd, MR; McMahon, JB (2004). "Neamphamide A. A new HIV-inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi". J. Nat. Prod. 67 (8): 1407–11. doi:10.1021/np040003f. PMID 15332865.
• callipeltin A Zampella, A; D'Auria, MV; Paloma, LG; Casapullo, A; Minale, L; Debitus, C; Henin, Y (1996). "Callipeltin A, an Anti-HIV Cyclic Depsipeptide from the New Caledonian Lithistida Sponge Callipelta sp.". J. Am. Chem. Soc. 118 (26): 6202–9. doi:10.1021/ja954287p.
• mirabamides A-D Plaza, A; Gustchina, E; Baker, HL; Kelly, M; Bewley, CA (2007). "Mirabamides A-D. Depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion". J. Nat. Prod. 70 (11): 1753–60. doi:10.1021/np070306k. PMID 17963357.; Andjelic, CD; Planelles, V; Barrows, LR (2008). "Characterizing the Anti-HIV Activity of Papuamide A." Mar Drugs. 6 (4): 528–49. doi:10.3390/md20080027. PMC 2630844. PMID 19172193.