Cyclic heptapeptide

Strongly hepatotoxic cyclic heptapeptides produced by some species of freshwater cyanobacteria (blue-green algae) (28). These microcystins represent a health risk to humans through drinking water, since they have been found to act as tumor promoters (29). Several chromatographic analytical procedures for microcystins have been... 

Figure 8. Left The cyclic heptapeptide hepatotoxin microcystin-LA (cyanoginosin-LA) produced by the colonial cyanobacterium Microcystis aeruginosa strain WR-70 (UV-010). MW = 909. Right The cyclic heptapeptide hepatotoxin microcystin-LR (cyanoginosin-LR) produced by a waterbloom of the colonial cyanobacterium Microcystis aeruginosa collected in Lake Akersvatn, Norway, 1984-85 MW=994, 69J1).

Hepatotoxins include microcystins, which are cyclic heptapeptides (Fig. 5.1a) and cylindrospermopsin, a sulfated guanidinium alkaloid (Fig. 5. lb). Microcystins bind to certain protein phosphatases responsible for regulating the distribution of cytoskeletal proteins (Zurawell et al. 2005 Leflaive and Ten-Hage 2007). Hepatocytes exposed to microcystins eventually undergo cellular deformation, resulting in intra-hepatic bleeding and, ultimately, death (Carmichael 2001 Batista et al. 2003). In contrast, cylindrospermopsin appears to have a different mode of activity, possibly involving inhibition of protein or nucleotide synthesis (Codd et al. 1999 Froscio et al. 2003 Reisner et al. 2004). Nevertheless, microcystins are the most common cyanotoxins isolated from cyanobacterial blooms (Sivonen and Jones 1999). 

Fig. 5.1 Common cyanobacterial hepatotoxins. (a) Generalized structure of microcystin, a cyclic heptapeptide. Note that X and Z are L-amino acids. For example, microcystin-LR possesses lysine and arginine residues at X and Z, respectively, (b) Cylindrospermopsin, a hepatotoxic alkaloid from Cylindrospermopsis raceborskii...

Table 5 Examples for the Synthesis of Cyclic Heptapeptides and Larger Systems 11136309327 329 ...

The Panamanian marine area has afforded unique microbial metabolites. Unusual polyene polyketides, the macrolactins, were isolated from a deep-sea bacterium in culture. Unfortunately the strain has been lost, or has lost viability (Rychnovsky1992). Unique cyclic heptapeptides, the cyclomarins, were obtained from the culture of an actinomycete, Streptomyces sp., isolated from sediments. The uniqueness of these metaboEtes contradicts the common assumption of scarce boundaries posed to microbial species m the sea. 

Carroll, A.R. Bowden, B.F. Coll, J.C. Hockless, D.C.R. Skelton, B.W. White, A.H. (1994) Mollamide, a cytotoxic cyclic heptapeptide from the compound ascidian Didemnum molle. Aust. J. Chem., 47,61-69. 

Kong, F. Burgoyne, D.L. Andersen, R.J. Allen, T.M. (1992)Pseudoaxinellin, a cyclic heptapeptide isolated from the Papua New Guinea sponge Pseudoaxinella massa. Tetrahedron Lett., 33, 3269-72. 

A. General description Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Eptifibatide binds to the platelet receptor glycoprotein (gp) Ilb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophifized. 

Okinawa contained a cytotoxic, cyclic heptapeptide, cupolamide (442) [368]. 

Figure 7.26 The structure of the hepatotoxic cyclic heptapeptide microcystin LR. L-Arginine and L-leucine are variable amino acids. The reactive unsaturated group is indicated by the star. Abbreviations Adda, amino-methoxy-trimethyl-phenyl-decadienoic acid Mdha, methyldehydro-alanine Masp, methyl D-/so-aspartate D-Glu, D-/soglutamate D-Ala, D-alanine.

Synthetic peptides containing side-chain modification have also been used as molecular scaffolds for the preparation of multiple receptors and molecular devices. 5 These include the use of crown ethers, cyclodextrins, porphyrins, and peptides with metal-binding sites (including ferrocenyl and EDTA side chains) (Section 9.4). Cyclization procedures have been developed to prepare biologically active cycloisodityrosine peptides which contain 14-or 17-membered rings (Section 9.5). The use of tryptathionine, a cross-linking dipeptide consisting of side-chain-to-side-chain linked L-Trp-L-Cys that is present in phallotoxins, 6 a family of cyclic heptapeptides, is also described (Section 9.6). 

The poisonous components of the most deadly mushroom Amanita phalloides (the Death Cap) are bicyclic heptapeptides which have an additional covalent bond that connects the ( -sulfur atom of an l-cysteine residue with the carbon atom in position 2 of the indole ring of the L-tryptophan. Phalloidin (or phalloidine) is the most abundant member of a whole family of related cyclic heptapeptides called phallotoxins (for a review, see Wieland1 1). These poisonous peptides, therefore, contain a cross-linking moiety consisting of L-tryptophan coupled to L-cysteine, designated tryptathionine (1), alternatively called 5-(trypto-phan-2-yl)cysteine or 2-(L-3-alanylsulfenyl)-L-tryptophan (Scheme 1). 

Colistin (COL) is a multicomponent antibiotic (polymyxins E) that is produced by strains of inverse Bacillus polymyxa. It consists of a mixture of several closely related decapeptides with a general structure composed of a cyclic heptapeptide moiety and a side chain acetylated at the N-terminus by a fatty acid. Up to 13 different components have been identified. The two main components of colistin are polymyxins El and E2 they include the same amino acids but a different fatty acid (216). A selective and sensitive HPLC method was developed for the determination of COL residues in milk and four bovine tissues (muscle, liver, kidney, and fat). The sample pretreatment consists of protein precipitation with trichloracetic acid (TCA), solid-phase purification on Cl 8 SPE cartridges, and precolumn derivatization of colistin with o-phthalaldehyde and 2-mercaptoethanol in borate buffer (pH 10.5). The last step was performed automatically, and the resulting reaction mixture was injected into a switching HPLC system including a precolumn and the reversed-phase analytical column. Fluorescence detection was used. The structural study of El and E2 derivatives was carried out by HPLC coupled with an electrospray MS. Recoveries from the preseparation procedure were higher than 60%. 

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

Polymyxin B, (Section 16.1.6) is a cyclic heptapeptide with a pendent tripeptide segment that has topical antibiotic properties. The solid-phase synthesis is carried out with appropriate side-chain protections. The linear heptapeptide is removed from the resin and cyclized to yield the polymyxin B,. The synthesis of the peptidomimetic (S)-6-methyloctanoic acid is also outlined.136 ... 

Dubost, D., Kaufman, M., Zimmerman, J., Bogusky, M. J., Coddington, A. B., Pitzenberger, S. M. Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient induced oxidation. Pharm Res 13 1811-1814 (1996). 

D.P. Botes, A.A. Tuinmann, P.L. Wessels, C.C. Viljoen, H. Kruger, D.H. Williams, S. Santikarn, R.J. Smith and S.J. Hammond, The structure of cyanoginosin-LA, a cyclic heptapeptide toxin from the cyanobacterium Microcystis aeruginosa, J. Chem. Soc. Perkin Trans., 1 (1984) 2311-2318. 

W.W. Carmichael, V. Beasley, D.L. Bunner, J.N. Eloff, I.R. Falconer, P. Gorham, K.-I. Harada, T. Krishnamurthy, Y. Min-Juan, R.E. Moore, K. Rinehart, M. Runnegar, O.M. Skulberg and M. Watanabe, Naming of cyclic heptapeptide toxins of cyanobacteria (blue-green algae), Toxicon, 26 (1988) 971-973. 

T Nishizawa, M Asayama, K Fujii, K Herada, M Shirai. Genetic analysis of the peptide synthetase genes for the cyclic heptapeptide microcystin in Microcystis spp. J Biochem (Tokyo) 126 520-529, 1999. 

Structure Antibody Fab fragment Nonpeptide mimetic Cyclic heptapeptide... 

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