Depsipeptide Explained

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.[1] 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] 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.[3]

Depsipeptide natural products

thumb|right|222px|Enterochelin is a depsipeptide that is an iron-transporter.[4] Several depsipeptides have been found to exhibit anti-cancer properties.[5]

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.[6]

Etamycin was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model.[7] Several depsipeptides from Streptomyces exhibit antimicrobial activity.[8] [9] 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.[10] [11] [12]

Depsipeptides can be formed through a Passerini reaction.

References

  1. Avan . Ilker . Tala . Srinivasa R. . Steel . Peter J. . Katritzky . Alan R. . Benzotriazole-Mediated Syntheses of Depsipeptides and Oligoesters . The Journal of Organic Chemistry . 17 June 2011 . 76 . 12 . 4884–4893 . 10.1021/jo200174j . 21452874 .
  2. Avan . Ilker . Hall . C. Dennis . Katritzky . Alan R. . Peptidomimetics via modifications of amino acids and peptide bonds . Chemical Society Reviews . 2014 . 43 . 10 . 3575–3594 . 10.1039/C3CS60384A . 24626261 .
  3. Recent Progress of the Synthetic Studies of Biologically Active Marine Cyclic Peptides and Depsipeptides. Yasumasa Hamada . Takayuki Shioiri . Chem. Rev.. 2005. 105. 12. 4441–4482. 10.1021/cr0406312. 16351050.
  4. Walsh . Christopher T. . Jun Liu . Frank Rusnak . Masahiro Sakaitani . Molecular Studies on Enzymes in Chorismate Metabolism and the Enterobactin Biosynthetic Pathway . . 90 . 1990 . 1105–1129 . 10.1021/cr00105a003 . 7.
  5. Anticancer Drugs. 2015. 26. 259–71. 10.1097/CAD.0000000000000183. Cyclic depsipeptides as potential cancer therapeutics. Kitagaki, J. . Shi, G. . Miyauchi, S. . Murakami, S. . Yang, Y. . 3. 25419631 . 22071968 .
  6. 10.1021/jm0703800 . The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor . 2007 . Yurek-George . Alexander . Cecil . Alexander Richard Liam . Mo . Alex Hon Kit . Wen . Shijun . Rogers . Helen . Habens . Fay . Maeda . Satoko . Yoshida . Minoru . Packham . Graham . Ganesan . A. . Journal of Medicinal Chemistry . 50 . 23 . 5720–5726 . 17958342. 8 .
  7. Journal of Antibiotics . 63 . 2010 . 219–24 . 10.1038/ja.2010.22 . Activity of the streptogramin antibiotic etamycin against methicillin-resistant Staphylococcus aureus . Haste . Nina M . Perera . Varahenage R . Maloney . Katherine N . Tran . Dan N . Jensen . Paul . Fenical . William . Nizet . Victor . Hensler . Mary E . 5. 2889693 . 20339399.
  8. K. H. Michel, R. E. Kastner (Eli Lilly and Company), US 4492650, 1985 [Chem. Abstr. 1985, 102, 130459]
  9. Osada . Hiroyuki . Yano . Tatsuya . Koshino . Hiroyuki . Isono . Kiyoshi . 1991 . Enopeptin A, a novel depsipeptide antibiotic with anti-bacteriophage activity . The Journal of Antibiotics . 44 . 12. 1463–1466 . 10.7164/antibiotics.44.1463. 1778798 . free .
  10. Li . Him Shun . Dominic . Guarné . Alba . Maurizi . Michael R. . Cheng . Yi-Qiang . Wright . Gerard D. . Ghirlando . Rodolfo . Joseph . Ebenezer . Gloyd . Melanie . Seon Chung . Yu . Ortega . Joaquin . 2010 . Acyldepsipeptide Antibiotics Induce The Formation Of A Structured Axial Channel In ClpP: A Model For The ClpX/ClpA-Bound State Of ClpP . Chemistry & Biology . 17 . 9. 959–969 . 10.1016/j.chembiol.2010.07.008 . 20851345 . 2955292.
  11. Hinzen . Berthold . Heike Brötz-Oesterhelt . Labischinski . Harald . Brötz-Oesterhelt . Heike . Endermann . Rainer . Benet-Buchholz . Jordi . Hellwig . Veronica . Häbich . Dieter . Schumacher . Andreas . Lampe . Thomas . Paulsen . Holger . Raddatz . Siegfried . 2006 . Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics . ChemMedChem . 1 . 7. 689–693 . 10.1002/cmdc.200600055 . 16902918. 36525372 .
  12. Carney . Daniel W. . Schmitz . Karl R. . Truong . Jonathan V. . Sauer . Robert T. . Sello . Jason K. . 2014 . Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity . Journal of the American Chemical Society . 136 . 5 . 1922–1929 . 10.1021/ja410385c. 24422534 . 4004210 . free .

Further reading

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