Undecapeptide

Price S L, R J Harrison and M F Guest 1989. An Ab Initio Distributed Multipole Study of the Electrostatic Potential Around an Undecapeptide Cyclosporin Derivative and a Comparison with Point Charge Electrostatic Models. Journal of Computational Chemistry 10 552-567. 

The purity of the peptide finally obtained depends critically on the yield of each cycle. It must be extraordinarily good to produce even moderately pure products (K. Ltibke, 1975). If the average yield of amide formadon in the synthesis of an undecapeptide (n = 10) is. for example, 98< to, the product will contain already about 20% of different impurities which may be difficult to remove. 

Ecample Miller and Rich investigated the conformational consequences of substitutions on an amino acid in cyclosporin A, an important immunosuppressive drug. One of the amino acids in this cyclic undecapeptide is (2, 3r, 4r, 6e)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt). It is essential for biological activity. 

Tachykinins and Substance P. The tachykinins (82) include the undecapeptide, substance P,... 

A two-site immunometric assay of undecapeptide substance P (SP) has been developed. This assay is based on the use of two different antibodies specifically directed against the N- and C-terminal parts of the peptide (95). Affinity-purified polyclonal antibodies raised against the six amino-terminal residues of the molecule were used as capture antibodies. A monoclonal antibody directed against the carboxy terminal part of substance P (SP), covalently coupled to the enzyme acetylcholinesterase, was used as the tracer antibody. The assay is very sensitive, having a detection limit close to 3 pg/mL. The assay is fiiUy specific for SP because cross-reactivity coefficients between 0.01% were observed with other tachykinins, SP derivatives, and SP fragments. The assay can be used to measure the SP content of rat brain extracts. 

A secondary metabolite produced by Tolypocladium inflation. This fungus was initially isolated in a soil sample collected in Norway. Cyclosporin A is a cyclic undecapeptide. Inside cells, cyclosporine A binds its immunophillin receptor known as cyclophillin. Like the FK506-FKBP12 complex, cyclosporin A-cyclophillin binds and inhibits the protein phosphatase calcineurin. 

NMR 3D structure of the undecapeptide U-II generated a ligand pharmacophore hypothesis that served as query for the virtual screening of the Aventis in-house compound repository. Active leads from six different chemical classes could be identihed by the 3D search, for example, compound 17 (ECso = 400nM Fig. 16.2) [91]. 

The full potenhal of RDCs, however, can be seen by the incorporation of RDC data in structure calculations. Several programs hke XPLOR-NIH, DISCOVER or GROM ACS allow the incorporation of RDCs as angular or combined angular and distance dependent restraints. Several studies on sugars have been reported (see, e.g. Ref [43] and references therein) and Fig. 9.8 shows the comparison of three structural models for the backbone of the cyclic undecapeptide cyclosporin A, derived from X-ray crystahography, ROE data in CDCI3 as the solvent, and RDCs and ROEs obtained in a PDMS/CDCfi stretched gel [22]. Due to the sensitivity to... 

The CD1 method was also used in a block condensation to give a hexapeptide from a tetrapeptide and a dipeptide,[13] as well as an undecapeptide from a pentapeptide and a hexapeptide.[13] Further syntheses of peptides with the CDI method are described in references [14]-[16]. 

Opioid tetrapetide Opioid pentapeptide Octapetide Nonapeptide Tachykinin decapeptide Tachykinin undecapeptide Trisdecapeptide Opioid hexadecapeptide Opioid heptadecapeptide... 

A different strategy for measuring protease activity is based on the property of xanthene dyes to form H-type dimers (see Sect. 6.2.3) when they are in close proximity. These dimers are accompanied with a characteristic quenching of their fluorescence and, particularly for rhodamines, with a blue shift in the absorption spectrum [121, 122]. The probe D-NorFES-D designed to measure activity of elastase in HL-60 cells consists of an undecapeptide derivatized with one tetramethylrhodamine dye on each side. The sequence contains proline residues to create a bent structure and bring the two fluoro-phores in close proximity. Intact D-NorFES-D shows 90% of its fluorescence quenched plus a blue shift of the absorption spectrum. After addition of the serine protease elastase, an increase in the fluorescence and a bathochromic shift of the absorption spectrum is observed, resulting in an increase in the emission ratio [80],... 

Substance P, an undecapeptide, is abundant both in the periphery and in the central nervous system. It is usually co-localized with one of the classical neurotransmitters, most commonly serotonin. Substance P is thought to have a role in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. The substance-P-preferring receptor neurokinin-1 has been focused on most intensively in drug development, and existing... 

Using the Multipin method, Gilbertson then synthesized 27 undecapeptides on solid phase, which were presumed to have a helical conformation. This was induced by frequent use of the a-alkylated amino acid aminoisobutyric acid. The phosphine-thiooxide-containing residues were positioned in the i and i + 4 positions, which would lead to the two phosphines being adjacent in the helical peptide chain. In addition, Gilbertson synthesized 36 peptides containing phosphines in the i and i + 1 positions. 

Scheme 36.9 Libraries of phosphine-containing helical undecapeptides.

This example illustrates that the reactivity of peptide bonds involving serine residues is not due solely to the presence of serine other, as yet poorly understood factors must also play a role. Threonine residues also show this particular type of reactivity [9]. Here, we examine the case of cyclosporin A (CsA), a cyclic undecapeptide that contains some unusual amino acids (6.57, Fig. 6.23), whose major breakdown reaction is hydrolytic cleavage at a threonine analogue. Position 1 is occupied by 4-[( )-but-2-enyl]-A,4-dimethyl-threonine, whose OH group reacts as a nucleophile at the carbonyl C-atom of the adjacent A-methylvalinc (position 11) [86],... 

Early investigations of peptides in membrane model systems included studies of mel-letin 124,125 220 221 spectra and polarization properties. This water-soluble peptide is found to be structureless in solution at neutral pH but was sensitive to environmental change. The undecapeptide hormone, substance P, a member of the tackykinin family, was also found by Choo et a].1222 to be unstructured in solution at physiological pH and to aggregate at high pH or on interaction with charged lipids. These data were used as counter-evidence to a hypothesis that the membrane surface structured the peptide to facilitate interaction with the receptor. 

Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and are decapeptides. 

Hanessian et al. 157 again utilized the indolizidinone skeleton to mimic the proposed (3-turn in the -Trp-Phe-Gly-Leu- sequence of the undecapeptide substance P. The compound 112 (Scheme 40) had no affinity for the NK1 receptor and low affinity for the recombinant human NK2 receptor. 

As mentioned above, the photochemically induced Pr - Pfr transformation manifests itself in the bilatriene chromophore, when still attached to the undecapeptide fragment, solely by the Z,E isomerism of the C(15) double bond in the Pr and Pfr froms (cf. Figure 5) [42,43], It is not yet known whether the chromophore in the intact Pfr chromoprotein differs additionally from the Pr chromophore with regard to the configuration of any of the other two exocyclic double bonds and/or the conformation. 

A two-site immunometnc assay of undecapeptide substance P (SP) has been developed. A number of solid-phase automated immunoassay analyzers have been used for performing immunoassays, A number of immunoassay methods have been found useful for environmental analysis (see Automated Instrumentation). 

Cyclosporin (Section 16.1.3) is an undecapeptide that acts as a potent immunosuppressant. Seven of its eleven residues are N-methylated. Its synthesis in solution was carried out by a series of segment condensations)32,33 The didemnins (Section 16.1.4) are isolated from marine organisms known as tunicates. Their therapeutic potential lies in applications as antitumor, antiviral, and immunosuppressant agents. The didemnin family of natural products contains peptidomimetic residues including A,0-dimethyltyrosine-proline and leucine—2-(hydroxyisovaleryl)propionic acid and (4-hydroxy)-2,5-dimethyl-3-oxo-... 

Substance P and neurokinin 1 receptors. The first neurokinin was discovered in the 1930s in extracts of brain or intestine. Since it was prepared as a powder, it was called substance P. This molecule is now known to be a string of 11 amino acids (an undecapeptide) (Fig. 5—67). This is in sharp contrast to monoamine neurotransmitters, which are modifications of a single amino acid. 

Some small peptide-heme complexes have been prepared, including an undecapeptide (residues 11-21)668"669 and an octapeptide (residues 14-21). TTiese are useful models as they include the two cysteine residues that covalently link the heme to the peptide, and one of the axial ligands. The axial Met-80 residue is absent, but the position can be filled by methionine or by other ligands as required.670 Work with several octapeptide complexes shows that the rates of outer-sphere electron transfer appear to be independent of the axial ligand, and faster than the reaction for cytochrome c. Other comparisons show that the orientation of the axial methionine in cytochrome c and the contacts between heme and protein are important controlling factors in the electronic structure of the heme. Aqua and hydroxo complexes of iron(III) octapeptide complexes are also useful models for studying spin equilibria in iron(III) hemoproteins.671... 

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