共查询到20条相似文献,搜索用时 11 毫秒
1.
M. Crisma J.R. Deschamps C. George J.L. Flippen‐Anderson B. Kaptein Q.B. Broxterman A. Moretto S. Oancea M. Jost F. Formaggio C. Toniolo 《Chemical biology & drug design》2005,65(6):564-579
Abstract: 2,2,6,6‐Tetramethylpiperidine‐1‐oxyl‐4‐amino‐4‐carboxylic acid (TOAC) is a topographically and conformationally restricted, nitroxide containing, Cα‐tetrasubstituted α‐amino acid. Here, we describe the molecular and crystal structures, as determined by X‐ray diffraction analyses, of a TOAC terminally protected derivative, the cyclic dipeptide c(TOAC)2·1,1,1,3,3,3‐hexafluoropropan‐2‐ol (HFIP) solvate, and five TOAC‐containing, terminally protected, linear peptides ranging in length from tetra‐ to hepta‐peptides. Incipient and fully developed, regular or distorted 310‐helical structures are formed by the linear peptides. A detailed discussion on the average geometry and preferred conformation for the TOAC piperidine ring is also reported. The X‐ray diffraction structure of an intramolecularly cyclized side product resulting from a C‐activated TOAC residue has also been determined. 相似文献
2.
A. Moretto F. Formaggio M. Crisma C. Toniolo M. Saviano E. Benedetti R. Iacovino R.M. Vitale 《Chemical biology & drug design》2001,57(4):307-315
Abstract: Two complete series of N‐protected oligopeptide esters to the pentamer level from 1‐amino‐cyclodecane‐1‐carboxylic acid (Ac10c), an α‐amino acid conformationally constrained through a medium‐ring Cαi ? Cαi cyclization, and either the l ‐Ala or Aib residue, along with the N‐protected Ac10c monomer and homo‐dimer alkylamides, were synthesized using solution methods and fully characterized. The preferred conformation of these model peptides was assessed in deuterochloroform solution using FT‐IR absorption and 1H NMR techniques. Furthermore, the molecular structures of two derivatives (Z‐Ac10c‐OH and Fmoc‐Ac10c‐OH) and two peptides (the dipeptide ester Z‐Ac10c‐l ‐Phe‐OMe and the tripeptide ester Z‐Aib‐Ac10c‐Aib‐OtBu) were determined in the crystal state using X‐ray diffraction. The experimental results support the view that β‐bends and 310‐helices are preferentially adopted by peptides rich in Ac10c, the third largest cycloaliphatic Cα,α‐disubstituted glycine known. This investigation allowed us to complete a detailed conformational analysis of the whole 1‐amino‐cycloalkane‐1‐carboxylic acid (Acnc, with n = 3–12) series, which represents the prerequisite for our recent proposal of the ‘Acnc scan’ concept. 相似文献
3.
C. Peggion E. Mossel F. Formaggio M. Crisma B. Kaptein Q.B. Broxterman J. Kamphuis C. Toniolo 《Chemical biology & drug design》2000,55(3):262-269
Abstract: Using a chemo‐enzymatic approach we prepared the highly lipophilic, chiral, Cα‐methylated α‐amino acid (αMe)Aun. Two series of terminally protected model peptides containing either d ‐(αMe)Aun in combination with Aib or l ‐(αMe)Aun in combination with Gly were synthesized using solution methods and fully characterized. A detailed solution conformational analysis, based on FT‐IR absorption, 1H NMR and CD techniques, allowed us to determine the preferred conformation of this amino acid and the relationship between chirality at its α‐carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that d ‐(αMe)Aun favors the formation of the left‐handed 310‐helical conformation. 相似文献
4.
A. Moretto C. Peggion F. Formaggio M. Crisma C. Toniolo C. Piazza B. Kaptein Q.B. Broxterman I. Ruiz M.D. Diaz‐de‐Villegas J.A. Galvez C. Cativiela 《Chemical biology & drug design》2000,56(5):283-297
Abstract: Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Cα‐methylated α‐amino acid l ‐(αMe)Nva with a short, linear side‐chain. A set of terminally protected model peptides to the pentamer level containing either (αMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (αMe)Nva peptides were also synthesized using side‐chain hydrogenation of the corresponding Cα‐methyl, Cα‐allylglycine (Mag) peptides. A detailed solution and crystal‐state conformational analysis based on FT‐IR absorption, 1H NMR and X‐ray diffraction techniques allowed us to define that: (i) (αMe)Nva is an effective β‐turn and 310‐helix former; and (ii) the relationship between (αMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. l ‐(αMe)Nva induces the preferential formation of right‐handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on α‐amino acids with a Cα‐methyl substituent and a Cα‐linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures. 相似文献
5.
L. G. J. Hammarstrm T.J. Gauthier R.P. Hammer M.L. McLaughlin 《Chemical biology & drug design》2001,58(2):108-116
Abstract: A series of short, amphipathic peptides incorporating 80% Cα,Cα‐disubstituted glycines has been prepared to investigate amphipathicity as a helix‐stabilizing effect. The peptides were designed to adopt 310‐ or α‐helices based on amphipathic design of the primary sequence. Characterization by circular dichroism spectroscopy in various media (1 : 1 acetonitrile/water; 9 : 1 acetonitrile/water; 9 : 1 acetonitrile/TFE; 25 mm SDS micelles in water) indicates that the peptides selectively adopt their designed conformation in micellar environments. We speculate that steric effects from ith and ith + 3 residues interactions may destabilize the 310‐helix in peptides containing amino acids with large side‐chains, as with 1‐aminocyclohexane‐1‐carboxylic acid (Ac6c). This problem may be overcome by alternating large and small amino acids in the ith and ith + 3 residues, which are staggered in the 310‐helix. 相似文献
6.
A. Barazza A. Wittelsberger N. Fiori E. Schievano S. Mammi C. Toniolo J.M. Alexander M. Rosenblatt E. Peggion M. Chorev 《Chemical biology & drug design》2005,65(1):23-35
Abstract: The N‐terminal 1–34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N‐terminal fragments presenting the principal activating domain such as PTH(1–11) and PTH(1–14) with helicity‐enhancing substitutions yield potent analogues with PTH(1–34)‐like activity. To further investigate the role of α‐helicity on biological potency, we designed and synthesized by solid‐phase methodology the following hPTH(1–11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix‐promoting Cα‐tetrasubstituted α‐amino acids α‐amino isobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid (Ac5c) and 1‐aminocyclohexane‐1‐carboxylic acid (Ac6c): Ac5c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( I ); Aib‐V‐Ac5c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( II ); Ac6c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( III ); Aib‐V‐Ac6c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( IV ); Aib‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( V ); S‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( VI ), S‐V‐Ac5c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( VII ); Ac5c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( VIII ); Ac6c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( IX ); Ac5c‐V‐Ac5c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( X ); Ac6c‐V‐Ac6c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH2 ( XI ). All analogues were biologically evaluated and conformationally characterized in 2,2,2‐trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I – V , which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand‐stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III , VI and VII are very weakly active and analogues IV , V , VIII–XI are inactive. The most potent analogue, I exhibits biological activity 3500‐fold higher than that of the native PTH(1–11) and only 15‐fold weaker than that of the native sequence hPTH(1–34). Remarkably, the two most potent analogues, I and II , and the very weakly active analogues, VI and VII , exhibit similar helix contents. These results indicate that the presence of a stable N‐terminal helical sequence is an important but not sufficient condition for biological activity. 相似文献
7.
Abstract: A protected tridehydropeptide containing (Z)‐β‐(3‐pyridyl)‐α,β‐dehydroalanine (ΔZ3Pal) residue, Boc‐Leu‐ΔZ3Pal‐Leu‐OMe ( 1 ), was synthesized via Erlenmeyer azlactone method. X‐ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a ΔZPhe analog, Boc‐Leu‐ΔZPhe‐Leu‐OMe ( 2 ). 相似文献
8.
S.R. Haynes S.D. Hagins M.M. Juban P.H. Elzer R.P. Hammer 《Chemical biology & drug design》2005,66(6):333-347
Abstract: A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid‐phase synthetic techniques. Each nonapeptide was rich in α,α‐dialkylated amino acids [one 4‐aminopiperidine‐4‐carboxylic acid (Api) and six α‐aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9‐fluorenylmethyloxycarbonyl (Fmoc)‐Aib‐Aib‐OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 310‐helical, amphipathic design of these peptides was born out most prominently in the N‐terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations ≤100 μm ) and the acetylated peptides (concentrations ≤200 μm ) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages. 相似文献
9.
G. VALLE M. CRISMA C. TONIOLO. S. POLINELLI W. H. J. BOESTEN H. E. SCHOEMAKER E. M. MEIJER J. KAMPHUIS 《Chemical biology & drug design》1991,37(6):521-527
The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral Cα,α-disubstituted glycine Cα-methyl, Cα-isopropylglycine [(αMe)Val] have been determined by X-ray diffraction. The derivative is mClAc-l -(α Me)Val-OH, and the peptides are Z-l -(αMe)Val-(l -Ala)2-OMe monohydrate, Z-Aib-L-(αMe)Val-(Aib)2-OtBu, and Ac-(Aib)2-l -(αMe)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I β-turn conformation stabilized by a 1 ← 4N-H . O=C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 310-helices. All four L-(αMe)Val residues prefer φ, Ψ angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (αMe)Val residue is a strong type-I/III β-turn and helix former, and (ii) the relationship between (αMe)Val chirality and helix screw sense is the same as that of Cα-monosubstituted protein amino-acids. The implications for the use of the (αMe)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed. 相似文献
10.
MITSUNOBU DOI TOSHIMASA ISHIDA ALESSANDRA POLESE FERNANDO FORMAGGIO MARCO CRISMA CLAUDIO TONIOLO QUIRINUS B. BROXTERMAN JOHAN KAMPHUIS 《Chemical biology & drug design》1996,47(6):491-497
The molecular and crystal structures of the Cα-tetrasubstituted, δ-branched α-amino acid Cα-methyl-homophenylalanine, H-d -(αMe)Hph-OH, and three peptides (to the pentamer level), including the homotripeptide, have been determined by X-ray diffraction. The peptides are Z-l -(αMe)Hph-(l -Ala)2-OMe, pBrBz-[d -(αMe)Hph]3-OtBu and Ac-(Aib)2-l -(αMe)Hph-(Aib)2-OtBu. All the (αMe)Hph residues prefer φ,ψ torsion angles in the helical region of the conformational map. The two terminally blocked tripeptides adopt a β-bend conformation stabilized by a 1→4 C = O?H-N intramolecular H-bond. The terminally blocked pentapeptide is folded in a regular 310-helix. In general, the relationship between (αMe)Hph α-carbon chirality and helix handedness is the same as that exhibited by protein amino acids. A comparison is also made with the conclusions extracted from published work on peptides from other types of Cα-alkylated aromatic α-amino acids. © Munksgaard 1996. 相似文献
11.
C. TONIOLO M. CRISMA G.M. BONORA B. KLAJC F. LELJ P. GRIMALDI A. ROSA S. POLINELLI W.H.J. BOESTEN E.M. MEIJER H.E. SCHOEMAKER J. KAMPHUIS 《Chemical biology & drug design》1991,38(3):242-252
Conformational energy computations on Ac-l -(αMe)Val-NHMe indicate that turns and right-handed helical structures are particularly stable conformations for this chiral Cα-methyl, Cα-alkylglycyl residue. We have synthesized and characterized a variety of l -(αMe)Val derivatives and peptides (to the pentamer level). The results of the solution conformational analysis, performed using infrared absorption, 1H nuclear magnetic resonance, and circular dichroism, are in general agreement with those obtained from the theoretical investigation, in the sense that the l -(αMe)Val residue turns out to be a strong β-turn and right-handed helix former. A comparison is also made with the conclusions extracted from published work on peptides rich in other Cα-methyl, Cα-alkylglycyl residues. 相似文献
12.
Abstract: A brief survey of the history of peptide chemistry from Theodore Curtius to Emil Fischer to Bruce Merrifield is first presented. The discovery and development of peptide ligation, i.e. of actual chemical synthesis of proteins are described. In the main chapter, ‘ Synthesis of Proteins by Chemical Ligation ’ a detailed discussion of the principles, reactivities and mechanisms involved in the various coupling strategies now applied (ligation, chemical ligation, native chemical ligation) is given. These include coupling sites with cysteine and methionine (as well as the seleno analogs), histidine, glycine and pseudo‐prolines, ‘unrestricted’ amino‐acid residues (using the Staudinger reaction), as well as solid‐phase segment coupling by thioligation of unprotected peptides. In another section, ‘ Synthesis of β‐peptides by Thioligation ’, couplings involving β2‐ and β3‐peptides are described (with experimental details). 相似文献
13.
Abstract: Crystal structure analysis of a model peptide: Boc‐β‐Ala‐Aib‐β‐Ala‐NHCH3 (β‐Ala: 3‐amino propionic acid; Aib: α‐aminoisobutyric acid) revealed distinct conformational preferences for folded [φ≈136°, µ ≈ ?62°, ψ ≈100°] and semifolded [φ ≈ 83°, µ ≈ ?177°, ψ ≈ ?117°] structures of the N‐ and C‐terminus β‐Ala residues, respectively. The overall folded conformation is stabilized by unusual Ni···H‐Ni+1 and nonconventional C–H···O intramolecular hydrogen bonding interactions. 相似文献
14.
Abstract: During the manufacture of a proprietary peptide drug substance a new impurity appeared unexpectedly. Investigation of its chemical structure established the impurity as a β‐Ala insertion mutant of the mother peptide. The source of the β‐Ala was identified as contamination of the Fmoc‐Ala‐OH raw material with Fmoc‐β‐Ala‐Ala‐OH. Further studies also demonstrated the presence of β‐Ala in other Fmoc‐amino acids, particularly in Fmoc‐Arg(Pbf)‐OH. In this case, it was due to the presence of both Fmoc‐β‐Ala‐OH and Fmoc‐β‐Ala‐Arg(Pbf)‐OH. It is concluded that β‐Ala contamination of Fmoc‐amino acid derivatives is a general and hitherto unrecognized problem to suppliers of Fmoc‐amino acid derivatives. The β‐Ala is often present as Fmoc‐β‐Ala‐OH and/or as a dipeptide, Fmoc‐β‐Ala‐amino acid‐OH. In collaboration with the suppliers, new specifications were introduced, recognizing the presence of β‐Ala‐related impurities in the raw materials and limiting them to acceptable levels. The implementation of these measures has essentially eliminated β‐Ala contamination as a problem in the manufacture of the drug substance. 相似文献
15.
Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro
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Sourav Kumar Ashim Paul Sourav Kalita Anup Kumar Ghosh Bhubaneswar Mandal Amal Chandra Mondal 《Chemical biology & drug design》2017,89(6):888-900
Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid‐β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid‐β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β‐sheet breaker α/β‐hybrid peptide (BSBHp) and the underlying mechanisms against Aβ40‐induced neurotoxicity in human neuroblastoma SH‐SY5Y cells. Cells were pretreated with the peptide Aβ40 to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca2+, and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ40‐induced toxicity by retaining cell viability, suppressing generation of ROS, Ca2+ levels, and effectively protects neuronal apoptosis by suppressing pro‐apoptotic protein Bax and up‐regulating antiapoptotic protein Bcl‐2. These results suggest that α/β‐hybrid peptide has neuroprotective effects against Aβ40‐induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases. 相似文献
16.
Abstract: A new and efficient method for the synthesis ofNα‐Fmoc‐/Boc‐/Z‐β‐amino acids using the two‐step Arndt‐Eistert approach is described. Fmoc‐/Boc‐/Z‐α‐Amino acid fluorides were used for the acylation of diazomethane synthesizing Fmoc‐/Boc‐/Z‐α‐aminodiazoketones as crystalline solids with good yield and purity. They were then converted to the corresponding β‐amino acids using PhCOOAg/dioxane/H2O. 相似文献
17.
S. Roy H.‐G. Lombart W. D. Lubell R. E. W. Hancock S. W. Farmer 《Chemical biology & drug design》2002,60(4):198-214
Abstract: Indolizidin‐2‐one amino acids (I2aas, 6S‐ and 6R‐ 1 ) possessing 6S‐ and 6R‐ring‐fusion stereochemistry were introduced into the antimicrobial peptide gramicidin S (GS) to explore the relationships between configuration, peptide conformation and biological activity. Solution‐phase and solid‐phase techniques were used to synthesize three analogs with I2aa residues in place of the d ‐Phe‐Pro residues at the turn regions of GS: [(6S)‐I2aa4?5,4′?5′]GS ( 2 ), [Lys2,2′,(6S)‐I2aa4?5,4′?5′]GS ( 3 ) and [(6R)‐I2aa4?5,4′?5′]GS ( 4 ). Although conformational analysis of [I2aa4?5,4′?5′]GS analogs 2?4 indicated that both ring‐fusion stereoisomers of I2aa gave peptides with CD and NMR spectral data characteristic of GS, the (6S)‐I2aa analogs 2 and 3 exhibited more intense CD curve shapes, as well as greater numbers of nonsequential NOE between opposing Val and Leu residues, relative to the (6R)‐I2aa analog 4 , suggesting a greater propensity for the (6S)‐diastereomer to adopt the β‐turn/antiparallel β‐pleated sheet conformation. In measurements of antibacterial and antifungal activity, the (6S)‐I2aa analog 2 exhibited significantly better potency than the (6R)‐I2aa diastereomer 4 . Relative to GS, [(6S)‐I2aa4?5,4′?5′]GS ( 2 ) exhibited usually 1/2 to 1/4 antimicrobial activity as well as 1/4 hemolytic activity. In certain cases, antimicrobial and hemolytic activities of GS were shown to be dissociated through modification at the peptide turn regions with the (6S)‐I2aa diastereomer. The synthesis and evaluation of GS analogs 2?4 has furnished new insight into the importance of ring‐fusion stereochemistry for turn mimicry by indolizidin‐2‐one amino acids as well as novel antimicrobial peptides. 相似文献
18.
PATRICK van ROEY G. DAVID SMITH T.M. BALASUBRAMANIAN E.W. CZERWINSKI GARLAND R. MARSHALL F. SCOTT MATHEWS 《Chemical biology & drug design》1983,22(4):404-409
Boc-Pro-Aib-Ala-Aib-OMe crystallizes in the orthorhombic space group P21212 with cell dimensions a = 17.701 (3)Å, b = 17.476 (4)Å, c = 9.686 (2)Å, V = 2996.3 Å3. The first three residues form a single turn of a 310-helix stabilized by two intramolecular hydrogen bonds. Comparison of the conformation of the methyl ester of the tetrapeptide with that of its benzyl ester shows differences in the individual torsion angles of up to 29°, although the overall conformation is conserved. 相似文献
19.
Abstract: This review briefly surveys the conformational properties of guest ω‐amino acid residues when incorporated into host α‐peptide sequences. The results presented focus primarily on the use of β‐ and γ‐residues in αω sequences. The insertion of additional methylene groups into peptide backbones enhances the range of accessible conformations, introducing additional torsional variables. A nomenclature system, which permits ready comparisons between α‐peptides and hybrid sequences, is defined. Crystal structure determination of hybrid peptides, which adopt helical and β‐hairpin conformations permits the characterization of backbone conformational parameters for β‐ and γ‐residues inserted into regular α‐polypeptide structures. Substituted β‐ and γ‐residues are more limited in the range of accessible conformation than their unsubstituted counterparts. The achiral β,β‐disubstituted γ‐amino acid, gabapentin, is an example of a stereochemically constrained residue in which the torsion angles about the Cβ–Cγ (θ1) and Cα–Cβ (θ2) bonds are restricted to the gauche conformation. Hybrid sequences permit the design of novel hydrogen bonded rings in peptide structures. 相似文献
20.
MARK I. LIFF KENNETH D. KOPPLE ZHENPING TIAN ROGER W. ROESKE 《Chemical biology & drug design》1994,43(5):471-476
We have examined the effect of Cα-methyl groups on the conformational ensemble of GnRH analog peptides by comparing 1H 2D NMR data from two analogs, Ac-D-Nal1-D-4-Cl-Cα-Me-Phe2-D-Pal3-Ser4-Tyr5-D-Arg6-Leu7-Arg8-Pro9-D-Ala10-NH2(1)andAc-D-Nal1-D-4-CI-Cα-Me-Phe2-D-Pal3-Ser4-Cα-Me-Tyr5-D-Arg6-Leu7-Cα-Me-Arg8-Pro9-D-Ala10-NH2 (2). The two additional Cα-methyl groups in residues 5 and 8 of 2 do not influence significantly the pattern of the observable main chain NOE intensities, or of the backbone HN proton chemical shifts, which indicates that they do not produce global changes in the conformational ensemble of the peptide. A local change induced by the substitution was observed in the conformation at d -Arg8-Pro9. 相似文献