Didemnins are cyclic

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, Many depsipeptides have both peptide and ester linkages. Elimination of the N–H group in a peptide structure results ...

compounds isolated from a

tunicate A tunicate is a marine invertebrate animal, a member of the subphylum Tunicata (). It is part of the Chordata, a phylum which includes all animals with dorsal nerve cords and notochords (including vertebrates). The subphylum was at one time ca ...

(

ascidian Ascidiacea, commonly known as the ascidians, tunicates (in part), and sea squirts (in part), is a polyphyletic class in the subphylum Tunicata of sac-like marine invertebrate filter feeders. Ascidians are characterized by a tough outer "tunic" ...

, or sea-squirt) of the

genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...

'' Trididemnum'' (family of Didemnidæ) that were collected in the

Caribbean Sea The Caribbean Sea ( es, Mar Caribe; french: Mer des Caraïbes; ht, Lanmè Karayib; jam, Kiaribiyan Sii; nl, Caraïbische Zee; pap, Laman Karibe) is a sea of the Atlantic Ocean in the tropics of the Western Hemisphere. It is bounded by Mexico ...

. They were first isolated in 1978 at the

University of Illinois The University of Illinois Urbana-Champaign (U of I, Illinois, University of Illinois, or UIUC) is a public land-grant research university in Illinois in the twin cities of Champaign and Urbana. It is the flagship institution of the University ...

. Although more than nine didemnins (didemnins A-E, G, X and Y) have been isolated from the extract of ''Trididemnum solidum'', didemnin B is the one that possesses the most potent biological activities. It is a strong antiviral agent against both DNA and RNA

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

es such as herpes simplex virus type 1, a strong

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

that shows some potential in skin graft and is also very

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

. It shows strong activity against

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

s. Large amounts of didemnin B were chemically synthesized and it was advanced to

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s by the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

. It has completed phase II human

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

against

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

of the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

, advanced

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, and metastatic breast cancer. Unfortunately, the compound exhibited high

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

through a high incidence of

anaphylactic reactions Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

in patients and trials were terminated. The didemnin analog

plitidepsin Plitidepsin (also known as dehydrodidemnin B, marketed by PharmaMar, S.A. under the trade name Aplidin) is a chemical compound extracted from the ascidian ''Aplidium albicans''. It is currently undergoing clinical trial testing. It is a member of ...

was in phase II clinical trials as of 2003.

Biosynthesis

The biosynthesis of depsipeptide Didemnin is governed by a hybrid non-ribosomal peptide synthetase-polyketide synthetase (NRPS-PKS) pathway. The didemnin mega-synthetase consists of 10 proteins, of which 8 NRPS and 2 PKS, covering 13 modules in total.Xu Y.,''et al.'' ''J. Am. Chem. Soc'' 2012, ''20'', 8625–8632. https://doi.org/10.1021/ja301735a Biosynthesis Pathway Didemnin B

The proposed pathway of the biosynthesis of didemnin B starts on Did A. Modules 1 and 2 both incorporate a glycine on a β-OH fatty acid. On DidB, the adenylation (A) domain is loaded by pyruvate and subsequently reduced in its cis conformation by the ketoreductase (KR) domain, yielding the lactate bounded to the thiolation (T) domain. Monomodular didC incorporates proline, before tridomain didD elongates the peptide chain with 3 amino acids. The adenylation (A) domain of didD is loaded with leucine and subsequently N-methylated by the methyltransferase (MT) domain and converted into N-methylated D-leucine by the epimerase (E) domain. The N-methylated leucine is the only D-amino acid in didemnin B. The second module on didD incorporates threonine and the third module on the domain attached isoleucine, assembling the tetrapeptide (Pro)-(N-Me-D-Leu)-(Thr)-(Ile). DidE is a PKS, but lacks an acyltransferase (AT) domain. Module 8 on didE attaches a ketide-extended β-hydroxy-γ-isostatin. It is suggested that the didemnin PKS mobilizes AT domain FabD from a Fatty Acid Synthase (FAS), since there iis no AT domain present in the didemin genome. The DidF A domain is loaded with 2-oxoisovaleric acid and incorporates α-hydroxy acid 2-hydroxyisovaleric acid. Module 10 on PKS DidG adds a second round of malonate extension. The MT domain on DidG adds an α-methyl group to this residue. Monomodular domains DidH, DidI and DidJ elongate the chain with respectively leucine, proline and tyrosine. The two MT domains on DidJ methylates tyrosine twice, to yield N-methyl-O-methyl-tyrosine, finalizing the assembly of linear didemnin B. The Thioesterase (TE) domain on module DidJ releases the product in its cyclized form.

References

Depsipeptides

Biosynthesis

See also

References