Cyclic octapeptides

This mushroom produces the toxin, a-amanitin, a cyclic octapeptide having several modified amino acids and a central purine, which strongly binds to and inhibits RNA pal ii and thereby blocirs elongation. 

Iturins are a group of fungicidal cyclic lipopeptides produced by Bacillus subtilis m m m All members of this group are cyclic octapeptides with seven a-amino acids and a unique 13-amino fatty acid homologue of iturinic acid. The predominant iturin-A isomer, A2, contains the n-C14-isomer of iturinic acid (Itu) (Scheme 8). The synthesis of the molecule can be divided into two steps with the first stage consisting of the assembly of the linear octapeptide on solid phase followed by the backbone cyclization in solution. 

A. General description Octreotide is a long-acting cyclic octapeptide (molecular weight 1.0 kDa) with pharmacologic actions mimicking those of the natural hormone somatostatin. The usefulness of natural somatostatin is limited by its extremely short duration of action, which requires continuous infusion. Octreotide is a molecular form (an octapeptide with two D-amino-acid substitutions) that overcomes the problem of short duration of action. 

The fibers formed from cyclic octapeptides 94 and 95 by hydrogen bonds perpendicular to the average ring planes were discussed in Section 4.2.4. The presence of the hydrophobic side chains in the latter molecule enabled Ghadiri... 

Three cyclic octapeptides, patellamides A-C (21-23) were isolated from L. patella and cytotoxicity data for these compounds and for ulicyclamide (15) and ulithiacyclamide (16) against L1210 murine leukaemia cells and the human acute lymphoblastic leukaemia (ALL) cell line CEM were reported [52]. The structures of the patellamides were later reassigned on the basis of synthetic studies. The proposed structures of patellamides B (22) and C (23) were synthesised and the products were shown to differ from the natural products. This led to new structures being proposed [53,54]. Separate syntheses of... 

Ripka et al.[167 168l suggested that benzodiazepines of the type 138 (Scheme 52, experimental details given below) could serve as a mimetic of a (3-turn. This mimetic was incorporated into a cyclic octapeptide -containing analogue of the antibiotic peptide gramicidin S to provide 139 (Scheme 53). 

Examples of the way these two entirely different approaches compliment each other are developing in conformation studies with the hormones angiotensin, oxytocin, and vasopressin. In 1964 Craig, Harfenist, and Paladini (7) published the comparative half-escape times shown in Table I in 0.01N acetic acid and another series in Table II using a different membrane less porous and not as selective as the first. Oxytocin and vasopressin are cyclic octapeptides with an S-S linkage closing the ring at the 1-6 positions (5, 6). Their size is thus limited except for the side... 

In a different approach to the development of an artificial channel, Ghadiri and co workers [55] designed a cyclic octapeptide (68) composed of amino acids with alternating d and l configurations. The resulting flat macrocycle was... 

Perthamide B (1099) is a novel cyclic octapeptide found in a Theonella sp. sponge near Perth, Australia (1122). A collection of the Japanese sponge Halichon-dria cylindrata has afforded halicylindramides A-E (1100-1103), and the absolute configurations are shown (1123,1124). Each compound features a 4-bromophenyl-alanine residue. 

Williams DE, Patrick BO, Behrisch HW, van Soest R, Roberge M, Andersen RJ (2005) Dominicin, a Cyclic Octapeptide, and Laughine, a Bromopyrrole Alkaloid, Isolated from the Caribbean Marine Sponge Eurypon laughlini. J Nat Prod 68 327... 

Lambert and co-workers50 also synthesized a pair of cyclic octapeptides 82 and 83 and studied their propensity to form nanotubular aggregates (Fig. 5). A linear peptide was initially synthesized on SynPhase Crowns with a Rink amide handle by standard Fmoc chemistry. The first residue used was aspartic acid protected as the ct-allyl ester. The support-bound linear peptide was cyclized in a head-to-tail manner by deprotection of... 

T. Shimizu and Y. Tanaka, Ion-Sensitive Cyclic Octapeptides, Vol., Agency of Industrial Sciences and Technology, Japan, 1986, p. 6. 

The cyclic octapeptide cycfo-[-(D-Ala-L-Glu-D-Ala-L-Gln)2-] has been designed by Ghadiri and co-workers to generate a hydrogen-bonded organic nanotube having an internal diameter of approximately 0.7-0.8 nm (Fig. 20.1.5). 

The cyclic octapeptide SMS 201-995 from Sandoz Ltd./Switzerland 39 80 0 has a longer duration of action than native SST and inhibits the secretion of GH more selectively. Moreover, it enhances the hypoglycemic effect of insulin while simultaneously decreasing glucagon. 

The amatoxins are cyclic octapeptides composed only of L-amino acids and containing a sulfoxide group instead of the thioether bridge in phallotoxin. Over 90% of the fatal cases of mushroom poisoning can be traced back to the amatoxins. Wieland et al. 234) have shown that, in addition to the toxins, the death cup contains a low concentration of an antitoxic cyclic decapeptide antamanide 108. 

Eukaryotic cells contain at least four different DNA-dependent RNA polymerases. Their localization, cellular transcripts, and susceptibility to the cyclic octapeptide a-amanitin (derived from poisonous mushrooms) are shown in Table 11.3. a-Amanitin blocks the elongation phase of RNA synthesis. Although the structures of these enzymes are much more complex than that of the prokaryotic RNA polymerase, the basic mechanism is very similar to that of the prokaryotic enzyme. 

The MM-EPR approach has been used successfully in a number of recent studies [205,206 328 329]. The most novel is that of the solution structure refinement of a dicopper(II) compound of a cyclic octapeptide[205] which is only the second structure of a dicopper(II) compound of this type of biologically important ligand and the first of a metal compound of an artificial cyclic octapeptide. An important development in this area is a new method for the simulation of EPR spectra (SOPHE)[325,326], which allows the simulation of coupled EPR spectra of polynuclear species with more than two metal centers with any electron spin 0, based on sets of parameters similar to those discussed above. 

S, and 28S ribosomal RNA (Section 29.3.1). The other ribosomal RNA molecule (5S rRNA, Section 29.3.1) and all the transfer RNA molecules (Section 29.1.2) are synthesized by RNA polymerase III, which is located in the nucleoplasm rather than in nucleoli. RNA polymerase II, which also is located in the nucleoplasm, synthesizes the precursors of messenger RNA as well as several small RNA molecules, such as those of the splicing apparatus (Section 28.3.5). Although all eukaryotic RNA polymerases are homologous to one another and to prokaryotic RNA polymerase, RNA polymerase II contains a unique carboxyl-terminal domain on the 220-kd subunit this domain is unusual because it contains multiple repeats of a YSPTSPS consensus sequence. The activities of RNA polymerase II are regulated by phosphorylation on the serine and threonine residues of the carboxyl-terminal domain. Another major distinction among the polymerases lies in their responses to the toxin a -amanitin, a cyclic octapeptide that contains several modified... 

FIG. 6.18 Photoactive peptide made up of two flat, rtng-sh >ed cyclic octapeptides connected by azobenzene, and their cylindrical aggregates in the trans state (intermolecular aggregate) and in the ds state (intramolecular aggregate). (Reproduced from reference 102 with permission from Wiley-VCH). 

Although all eukaryotic RNA polymerases are homologous to one another and to prokaryotic RNA polymerase, RNA polymerase II contains a unique carboxyl-terminal domain on the 220-kd subunit called the CTD this domain is unusual because it contains multiple repeats of a YSPTSPS consensus sequence. The activity of RNA polymerase II is regulated by phosphorylation mainly on the serine residues of the carboxyl-terminal domain. Another major distinction among the polymerases lies in their responses to the toxin a-amanitin, a cyclic octapeptide that contains several modified amino acids. 

In an elegant recent study, a cyclic octapeptide was coadsorbed with the alkanethiols and sulphides on the gold surface (Figure 30). The peptide units form highly oriented... 

FIGURE 30. Incorporation of cyclic octapeptide nanotubes in gold-thiol monolayers. Reprinted with permission from Reference 279. Copyright (1997) American Chemical Society... 

F re 14.15 (a) X-ray structure of a model dimer repeat unit of peptide nanombes made up from the self-assembly of cyclic octapeptides in a p-sheet-Uke fashion (b) space filling view showing the central pore. ... 

The identification of distinct functions of the ssts has also been hampered by the lack of high-affinity antagonists. Recently the identification of novel disulfide-linked cyclic octapeptide antagonists of SST was described that contain a core structure of a DL-cysteine pair at positions 2 and 7 of the peptides (Bass et al. 1996). One of these peptide antagonists, [Ac-4-N02-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2], displays a binding affinity to SST2 comparable with that observed for the native hormone and reverses SST-mediated inhibition of cAMP in cells transfected with... 

The nuclei of all eukaryotic cells examined so far (e.g., vertebrate, Drosophila, yeast, and plant cells) contain three different RNA polymerases, designated I, II, and III. These enzymes are eluted at different salt concentrations during ion-exchange chromatography and also differ In their sensitivity to ct-amanitin, a poisonous cyclic octapeptide produced by some mushrooms (Figure 11-4). Polymerase I Is very insensitive to ct-amanitin polymerase II is very sensitive and polymerase III has intermediate sensitivity. 

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