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] 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).

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

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 entree 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 (HDAC); it was first isolated as a fermentation product from Chromobacterium violaceum by the Fujisawa Pharmaceutical Company.[2] 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 discovery of anticancer agents

The depsipeptide etamycin, a streptogramin-type of natural product from a marine actinomycete, was observed in 1990 to have an impact on aspects of mammalian gene expression, and a clinical trial was conducted in 1996 for its therapeutic potential against T-cell lymphoma.[3]

In antibacterial discovery

Etamycin, described above, was shown in preliminary data in 2010 to have potent activity against MRSA in a mouse model.[4] Several depsipeptides natural products from Streptomyces have been studied for their antimicrobial activity.[5][6] 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.[7][8] Research is still underway to modify ADEPs in order to construct an antibiotic with greater antimicrobial activity.[9]

In antiviral discovery

Several depsipeptides have been found to inhibit HIV, including papuamide,[10] neamphamide A,[11] callipeltin A,[12] and mirabamides A-D.[13][14]

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.[15] Depsipeptides have also been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics.

References

  1. ↑ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (1995) "depsipeptides".
  2. ↑ Yurek-George, Alexander; Cecil, Alexander Richard Liam; Mo, Alex Hon Kit; Wen, Shijun; Rogers, Helen; Habens, Fay; Maeda, Satoko; Yoshida, Minoru et al. (2007). "The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor". Journal of Medicinal Chemistry 50 (23): 5720–5726. doi:10.1021/jm0703800. PMID 17958342.
  3. ↑ Depsipeptide (NSC 630176), National Cancer Institute
  4. ↑ Haste, Nina M; Perera, Varahenage R; Maloney, Katherine N; Tran, Dan N; Jensen, Paul; Fenical, William; Nizet, Victor; Hensler, Mary E (2010). "Activity of the streptogramin antibiotic etamycin against methicillin-resistant Staphylococcus aureus". J. Antibiotics 63 (5): 219. doi:10.1038/ja.2010.22.
  5. ↑ K. H. Michel, R. E. Kastner (Eli Lilly and Company), US 4492650, 1985 [Chem. Abstr. 1985, 102, 130459]
  6. ↑ Osada, Hiroyuki, Tatsuya Yano, Hiroyuki Koshino, and Kiyoshi Isono. "Enopeptin A, a novel depsipeptide antibiotic with anti-bacteriophage activity." The Journal of Antibiotics 44.12 (1991): 1463-1466.
  7. ↑ Li, Dominic Him Shun, Alba Guarné, Michael R. Maurizi, Yi-Qiang Cheng, Gerard D. Wright, Rodolfo Ghirlando, Ebenezer Joseph, Melanie Gloyd, Yu Seon Chung, and Joaquin Ortega. "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 (2010): 959-969. Print.
  8. ↑ Hinzen, Berthold, Harald Labischinski, Heike Brötz-Oesterhelt, Rainer Endermann, Jordi Benet-Buchholz, Veronica Hellwig, Dieter Häbich, Andreas Schumacher, Thomas Lampe, Holger Paulsen, and Siegfried Raddatz. "Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics." ChemMedChem 1.7 (2006): 689-693. Print.
  9. ↑ Carney, Daniel W., Karl R. Schmitz, Jonathan V. Truong, Robert T. Sauer, and Jason K. Sello. "Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity." JACS 136 (2014): 1922-1929
  10. ↑ 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. 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. 1999;121:5899–5909
  11. ↑ Oku N, Gustafson KR, Cartner LK, Wilson JA, Shigematsu N, Hess S, Pannell LK, Boyd MR, McMahon JB. Neamphamide A. A new HIV-inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi. J. Nat. Prod. 2004;67(8):1407-11.
  12. ↑ Zampella A, D'Auria MV, Paloma LG, Casapullo A, Minale L, Debitus C, Henin Y. Callipeltin A, an Anti-HIV Cyclic Depsipeptide from the New Caledonian Lithistida Sponge Callipelta sp. J. Am. Chem. Soc. 1996;118:6202-9
  13. ↑ Plaza A, Gustchina E, Baker HL, Kelly M, Bewley CA. Mirabamides A-D. Depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion. J. Nat. Prod. 2007;70(11):1753-60
  14. ↑ Andjelic CD, Planelles V, Barrows LR. Characterizing the Anti-HIV Activity of Papuamide A. Mar Drugs. 2008;6(4):528-49
  15. ↑ E.g., B D Sykes, and M D Scott (1972) Nuclear Magnetic Resonance Studies of the Dynamic Aspects of Molecular Structure and Interaction in Biological Systems, Annual Review of Biophysics and Bioengineering, 1: 27-50, DOI: 10.1146/annurev.bb.01.060172.000331.