- Immunomodulatory peptides
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The invention relates to peptides derivatized with a hydrophilic polymer which, in some embodiments, bind to human FcRn and inhibit binding of the Fc portion of an IgG to an FcRn, thereby modulating serum IgG levels. The disclosed compositions and methods may be used in some embodiments, for example, in treating autoimmune diseases and inflammatory disorders. The invention also relates, in further embodiments, to methods of using and methods of making the peptides of the invention.
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- New regioselectivity in the cleavage of histidine-containing peptides by palladium(II) complexes studied by kinetic experiments and molecular dynamics simulations
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Palladium(II) complexes promote hydrolytic cleavage of amide bonds in N- acetylhistidylglycine (AcHis-Gly), N-acetylhistidine (AcHis), and their derivatives methylated at the N-1 or N-3 atom of imidazole. Methylation controls coordination of imidazole to palladium(II) and allows stereochemical analysis of the reactions. The complex [PdCl4]2- regioselectively cleaves the amide bond involving the carboxylic group of histidine, the bond His- Gly; the rate constants of cleavage are virtually the same when the peptides coordinate to palladium(II) via the N-1 and the N-3 atom. The complex [Pd(H2O)4]2+ cleaves, at comparable rates, the amide bonds involving both the carboxylic (His-Gly) and the amino (AcHis) groups of histidine in the acetylated dipeptide. This unprecedented reactivity is examined by theoretical calculations in which molecular dynamics and solution of Poisson- Boltzmann equation are combined in a new way. When the Pd(H2O)32+ group is attached to the N-1 atom, both scissile bonds can be cleaved by internal delivery of aqua ligands. When the Pd(H2O)32+ group is attached to the N- 3 atom, both scissile bonds can be cleaved by internal delivery of aqua ligands and by external attack of water; in some conformers the two modes of cleavage may be combined in the reaction mechanism. In both N-1 and N-3 linkage isomers internal delivery seems to be assisted by weak hydrogen bonding. The rate constants for cleavage by [Pd(H2O)4]2+ are approximately 10 times greater than those for cleavage by [PdCl4]2-. This difference is explained semiquantitatively by consideration of the aquation equilibria involving [PdCl4]2-. This study shows that kinetics and regioselectivity of peptide cleavage may be controlled simply by choosing ligands in palladium(II) complexes. This is another step in our development of simple metal complexes as artificial metallopeptidases.
- Parac, Tatjana N.,Ullmann, G. Matthias,Kosti?, Nenad M.
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p. 3127 - 3135
(2007/10/03)
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- Preparatory study for the synthesis of the starfish alkaloid imbricatine. Syntheses of 5-arylthio-3-methyl-L-histidines
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Chiral syntheses of 3-methyl-5-(phenylthio)-L-histidine (8a) and 3-methyl-5-(1-naphthalenylthio)-L-histidine (8b), selected as models for the asteroid alkaloid imbricatine (7), have been accomplished through a 10-step route starting from 4(5)-bromoimidazole (9). The key steps involved were methylation of 9, hydroxymethylation of 4-bromo-1-methyl-1H-imidazole (11), replacement of the 4-bromo group by an arylthio group in the aldehyde 14, and introduction of a chiral α-amino acid moiety into the chlorides 17a and 17b by the 'bis-lactim ether' method. The synthesis of the 4-(4-methoxybenzyl)thio analogue 17c, carried out in a similar manner, concluded formal syntheses of ovothiols A and C (1 and 3).
- Ohba,Mukaihira,Fujii
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p. 1784 - 1790
(2007/10/02)
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- Method for the production of amino terminus protected naturally occurring amino acids
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A method for the production of substantially 100% pure Nα-urethane protected amino acids is disclosed. This method eliminates the formation of di-peptide and tri-peptide contaminants. Reaction of blocking reagents at the carboxylate site on a protected peptide is prevented by the application of labile amino acid esters. Subsequent removal of the ester yields, in ultra-high purity, the Nα-protected amino acid. The substantially 100% pure Nα-urethane protected amino acid are also disclosed.
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- The Differentiation of ?- and τ- Derivatised Histidines
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Two simple methods of differentiating ?- and τ-derivatised histidines unambiguously are described.The first involves conversion into the two known im-methyl-L-histidines, which, to avoid all possible confusion arising from ambiguous nomenclature and previous work, have been correlated with N(α)-t-butyloxycarbonyl-N(?)-benzyloxymethyl-L-histidine, whose structure has been established by X-ray crystallography.The second method, which is appropriate for im-substituents of type RCH2-, involves the measurement of nuclear Overhauser effects.If the substituent is at the ?-position, the CH2 signal is enhanced if the low-field adjacent proton between the heterocyclic nitrogens is irradiated, but not if the high-field, more distant, ring proton is irradiated.If the substituent is at the τ-position, the CH2 signal is enhanced whichewer of the equidistant ring protons is irradiated.
- Colombo, Roberto,Colombo, Fabio,Derome, Adrew E.,Jones, John H.,Rathbone, Daniel L.,Thomas, David W.
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p. 1811 - 1816
(2007/10/02)
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