- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
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A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
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p. 161 - 175
(2007/10/03)
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- Cyclosporins
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Cyclosporins having anti-bacterial activity useful as immuno suppressive and anti-inflammatory agents are provided, such as undecapeptides of the formula (I) STR1 in which A1 is either derived from 2-carboxyazetidine, 2-carboxypyrrolidine or 2-carboxypiperidine, or is an amino acid residue STR2 wherein n is 0, 1 or 2, X represents an amino, methylamino, mercapto or hydroxy group, R represents hydrogen or an acyclic aliphatic hydrocarbon group and R' represents hydrogen or methyl; A2 is an amino acid residue STR3 wherein R1 is an acyclic aliphatic hydrogen group optionally substituted at the C1 position of the group R1 by an amino, methylamino, mercapto or hydroxy group, but with the proviso that when R1 is a group of less than four carbon atoms then A1 is a heterocyclic amino acid residue or is an amino acid residue --R'N--CH(CHR(CH2)n X)--CO-- wherein either (a) R is hydrogen or (b) R is an acyclic aliphatic hydrocarbon group and either n is O and X is an amino, methylamino or mercapto group, or n is 1 or 2 and X is an amino, methylamino, mercapto or hydroxy group; A3 is a sarcosine residue; A4 is an N-methyl-leucine residue; A5 is a valine residue; A6 is an M-methyl-leucine residue; A7 is an alanine residue; A8 is an alanine residue; A9 is an N-methyl-leucine residue; A10 is an N-methyl-leucine or sarcosine residue; and A11 is an N-methylvaline residue.
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- Peptides and medical use thereof
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Of therapeutic value in various contexts in which the cyclosporins are used, for example as anti-bacterial agents and particularly as immunosuppressive and anti-inflammatory agents, are acyclic undecapeptides having the formula (I) in which A1 is either derived from 2-carboxyazetidine, 2-carboxypyrrolidine or 2-carboxypiperidine, which may optionally be substituted on a ring carbon atom other than that at position 2 by an amino, methylamino, mercapto or hydroxy group and/or by an acyclic aliphatic hydrocarbon group, or is an amino acid residue STR1 wherein n is 0, 1 or 2, X represents an amino, methylamino, mercapto or hydroxy group, R represents hydrogen or an acyclic aliphatic hydrocarbon group and R' represents hydrogen or a methyl group; A2 is an amino acid residue STR2 wherein R1 is an acyclic aliphatic hydrocarbon group, for example of 1 to 6 carbon atoms, optionally substituted at the C1 position of the group R1 by an amino, methylamino, mercapto or hydroxy group; A3 is a sarcosine residue; A4 is an N-methyl-leucine residue; A5 is a valine residue; A6 is an N-methyl-leucine residue; A7 is an alanine residue; A8 is an alanine residue; Ag is an N-methyl-leucine residue; A10 is an N-methyl-leucine or sarcosine residue; and A11 is an N-methylvaline residue; or such an acyclic undecapeptide in which one or more of the terminal amino or methylamino and carboxy groups and any amino, methylamino, mercapto or hydroxy group present in A1 or A2 is in derivative form.
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- Synthesis of Peptides Containing Unnatural, Metal-Ligating Residues: Aminodiacetic Acid as a Peptide Side Chain
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Peptides possessing a pair of residues separated by one turn in the α-helical conformation and potentially capable of ligating a single metal ion in aqueous solution were designed.It was predicted that the resulting cross-link would shift toward α-helix the random coil/α-helix equilibrium.The syntheses of 10 peptides Ac-AdalAlamAdal(Ala4GluLys)n-NH2 where Adal is an L-α-amino acid residue with an aminodiacetic acid bearing side chain, -(CH2)lN(CH2CO2H)2 (with values of l, m and n as follows: 1, 2, 3 (1); 1, 3, 1 (2a); 1, 3, 2 (2b); 1, 3, 3 (2c); 2, 2, 3 (3); 2, 3, 3 (4); 3, 2 ,3 (5); 3, 3, 3 (6); 4, 2, 3 (7); 4, 3, 3 (8) are described using Boc chemistry on p-methylbenzhydrylamine resin.The aminodiacetic acid bearing residues were incorporated with side chains protected as the dibenzyl esters.To avoid side reactions, residues Adal for l=1 and 2 were incorporated by a block approach.Peptide structures were confirmed by observation of the predicted parent ions in the FAB MS.The circular dichroism spectra of several of these peptides that possess a pair of metal-ligating residues separated by two or three intervening residues have previously been shown to undergo changes on addition of metal ions consistent with appreciable enhancement of helix content.
- Ruan, Fuqiang,Chen, Yanqiu,Itoh, Katsumi,Sasaki, Tomikazu,Hopkins, Paul B.
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p. 4347 - 4354
(2007/10/02)
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