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1.
Felemez M Marwood RD Potter BV Spiess B 《Biochemical and biophysical research communications》1999,266(2):334-340
Adenophostin A is a glyconucleotide natural product with the highest known potency for the D-myo-inositol 1,4,5-trisphosphate receptor. Using synthetic adenophostin A we have investigated the macroscopic and microscopic protonation process of this compound by performing (31)P NMR, (1)H NMR, and potentiometric titration experiments. The logarithms of the first to the fourth stepwise protonation constants are, respectively, log K(1) = 8.48, log K(2) = 6.20, log K(3) = 4.96, and log K(4) = 3.80. The latter constant refers to the protonation equilibrium involving the N1 adenine nitrogen. From the microconstants the protonation fractions of each individual phosphate group can be calculated. Remarkably, the ionization state of the phosphates of adenophostin A at near physiological pH is very similar to those of inositol 1,4,5-trisphosphate, indicating that differences in phosphate charge cannot account for the high potency of this molecule. The analysis of the (1)H chemical shifts vs pH provided complementary conformational information. In particular, a slight "wrongway shift" of H1" can be related to the protonation of P2, thus indicating a short H1"-P2 distance. Our results are in line with a recently published model in which, however, a certain degree of constraint would keep the ribose 2'-phosphate moiety close to the glucose ring phosphates. 相似文献
2.
G. Vertuani M. Boggian A. Breveglieri G. Cavicchioni S. Spisani A. Scatturin 《Amino acids》1995,9(4):375-383
Summary In order to investigate the proper peptide backbone conformation able to elicit a biological activity, HCO-Met-Pro-Phe-OMe, HCO-Met-[COO]Leu-Phe-OMe, and HCO-Met-OLeu-Phe-OMe, analogues of the prototypical chemotactic peptide HCO-Met-Leu-Phe-OMe, were studied by CD and IR techniques. The results obtained comparing biological and conformational data evidence the critical presence of (i) the NH group at position 2, (ii) a rather flexible backbone, (iii) the chemical structure of the central residue which can affect the stability of a possible active conformer. 相似文献
3.
4.
S L Han J E Rivier H A Scheraga 《International journal of peptide and protein research》1980,15(4):355-364
Laser Raman spectroscopy has been used to study the conformations of somatostatin and some selected analogues in aqueous solution. The results indicate that the CS-SC dihedral angles of somatostatin and of these analogues (except [Ala3,14]-SS, which has no disulfide bond) are within 20 degrees of +/- 85 degrees, and the SS-CC dihedral angles are predominantly in the range of 50 degrees-180 degrees. Furthermore, from the behavior of the amide I' and amide III bands, it appears that somatostatin adopts a beta-pleated sheet structure, whereas its analogues are less ordered (to varying degrees). 相似文献
5.
R. F. F. Vieira F. Casallanovo E. M. Cilli A. C. M. Paiva S. Schreier C. R. Nakaie 《Letters in Peptide Science》2002,9(2-3):83-89
Spin-labeled analogues of bradykinin (BK) were synthesized containing the amino acid TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) either before Arg1 (TOAC0-BK) or replacing Pro3 (TOAC3-BK). Whereas the latter is inactive, the former retains about 70% of BK's activity in isolated rat uterus. A combined electron paramagnetic resonance (EPR)-circular dichroism(CD) approach was used to examine the conformational propertiesof the peptides in the presence of membrane-mimetic systems (negatively charged sodium dodecyl sulfate, SDS, and zwitterionicN-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, HPS). While the peptides bind to both monomeric and micellar SDS, no interaction occurs with HPS, evincing the contribution of electrostatic interactions. TOAC3-BK's EPR spectral lineshapes are broader than those of TOAC0-BK, indicating amore restricted degree of motion at position 3. Moreover, the motional freedom of both peptides decreased upon binding to SDS. BK and TOAC0-BK solution CD spectra indicate highly flexible conformations (possibly an equilibrium between rapidlyinterconverting forms), while TOAC3-BK's spectra correspondto a more ordered structure. SDS binding induces drastic changesin BK and TOAC0-BK spectra, indicating stabilization of similar folds. The micelle interface promotes a higher degree of secondary structure by favoring intramolecular hydrogen bonds. Incontrast, TOAC3-BK spectra remain essentially unchanged. These results are interpreted as due to TOAC's ring imposing a more constrained conformation. This rigidity is very likely responsible for the inability of TOAC3-BK to acquire the correct receptor-bound conformation, leading to loss of biological activity. On the other hand, the greater flexibility of TOAC0-BK and the similarity between its conformational behavior and that of the native hormone are probably related to their similar biological activity. 相似文献
6.
Vieira R. F. F. Casallanovo F. Cilli E. M. Paiva A. C. M. Schreier S. Nakaie C. R. 《International journal of peptide research and therapeutics》2002,9(2-3):83-89
Summary Spin-labeled analogues of bradykinin (BK) were synthesized containing the amino acid TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic
acid) either before Arg1 (TOAC0-BK) or replacing Pro3 (TOAC3-BK). Whereas the latter is inactive, the former retains about 70% of BK's activity in isolated rat uterus. A combined electron
paramagnetic resonance (EPR)-circular dichroism (CD) approach was used to examine the conformational properties of the peptides
in the presence of membrane-mimetic systems (negatively charged sodium dodecyl sulfate, SDS, and zwitterionic N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate,
HPS). While the peptides bind to both monomeric and micellar SDS, no interaction occurs with HPS, evincing the contribution
of electrostatic interactions. TOAC3-BK's EPR spectral lineshapes are broader than those of TOAC0-BK, indicating a more restricted degree of motion at position 3. Moreover, the motional freedom of both peptides decreased
upon binding to SDS. BK and TOAC0-BK solution CD spectra indicate highly flexible conformations (possibly an equilibrium between rapidly interconverting forms),
while TOAC3-BK's spectra correspond to a more ordered structure. SDS binding induces drastic changes in BK and TOAC0-BK spectra, indicating stabilization of similar folds. The micelle interface promotes a higher degree of secondary structure
by favoring intramolecular hydrogen bonds. In contrast. TOAC3-BK spectra remain essentially unchanged. These results are interpreted as due to TOAC's ring imposing a more constrained
conformation. This rigidity is very likely responsible for the inability of TOAC3-BK to acquire the correct receptor-bound conformation leading to loss of biological activity, On the other hand, the greater
flexibility of TOAC0-BK and the similarity between its conformational behavior and that of the native hormone are probably related to their similar
biological activity. 相似文献
7.
Conformational studies on synthetic repetitive sequences and analogues of elastin are described. CD and nmr measurements gave evidence of flexible beta-turns as the dominant structural feature whose stability was found to decrease by increasing the number of repetitive units. The sequences comprised the structural unit Gly-X-Gly (X = Val, Leu, Ala), with X-Gly or Gly-Gly located at the corners of the bend. Based on that, it is proposed that these regions of elastin, unlike the proline-containing sequences, contribute to the elasticity of the protein through a classical mechanism in terms of the rotational isomeric state theory. 相似文献
8.
Emilia A. Lubecka Emilia Sikorska Alina Marcinkowska Jerzy Ciarkowski 《Journal of peptide science》2014,20(6):406-414
Two glycosylated peptides have been studied using NMR spectroscopy supported by molecular modeling. Peptide I is an oxytocin (OT) analogue in which glutamine 4 was replaced by serine with attached α‐d ‐mannose through the oxygen β atom, whereas peptide II is a lysine‐vasopressin (LVP) analogue with lysine 8 side chain modified by the attachment of glucuronic acid through an amide bond. Both peptides exhibit very weak uterotonic effect and are less susceptible to proteolytic degradation than the mother hormones. Additionally, peptide II reveals very weak pressor and antidiuretic activities. Our results have shown that the conformational preferences of glycosylated analogues are highly similar to those of their respective mother hormones. OT glycosylated analogue (I) exhibits a 3,4 β‐turn characteristic of OT‐like peptides, and vasopressin‐glycosylated analogue (II) exhibits β‐turns typical of vasopressin‐like peptides. Therefore, the lack of binding of the glycosylated analogues to the receptors can be attributed to a steric interference between the carbohydrate moieties and the receptors. We also consider this to be the reason of the very low activity of the analyzed glycopeptides. We expect that results from these studies will be helpful in designing new OT‐like and vasopressin‐like drugs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
9.
Jeannot F Gosselin G Standring D Bryant M Sommadossi JP Giulia Loi A La Colla P Mathé C 《Bioorganic & medicinal chemistry》2002,10(10):3153-3161
3'-Deoxy-3'-C-CF3, 2',3'-dideoxy-3'-C-CF3 and 2',3'-unsaturated-3'-C-CF3 nucleoside derivatives of adenosine and cytidine have been synthesized. All these derivatives were prepared by glycosylation of adenine and uracil with a suitable peracylated 3-trifluoromethyl sugar precursor. The resulting protected nucleosides were subject to appropriate chemical modifications to afford the target nucleoside derivatives. Additionally, the chemical stability in acidic and neutral media of the 2',3'-dideoxy-3'-C-CF3 and 2',3'-unsaturated-3'-C-CF3 nucleoside derivatives of adenosine was compared to that of their parent nucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxy-2',3'-didehydroadenosine (d(4)A). Our results confirm that addition of a trifluoromethyl group at C-3' on such nucleoside derivatives appears to confer increased chemical stability toward acid-catalyzed cleavage of the glycosidic bond comparatively to their parent counterparts. When evaluated for their antiviral activity in cell culture experiments, two compounds, namely, 2',3'-dideoxy-3'-C-CF3-adenosine and 2',3'-dideoxy-2',3'-didehydro-3'-C-CF3-cytidine exhibited moderate anti-HBV activity with EC50 values of 10 and 5 microM, respectively. 相似文献
10.
Moraes LG Fázio MA Vieira RF Nakaie CR Miranda MT Schreier S Daffre S Miranda A 《Biochimica et biophysica acta》2007,1768(1):52-58
The aim of this work was to examine the bioactivity and the conformational behavior of some gomesin (Gm) analogues in different environments that mimic the biological membrane/water interface. Thus, manual peptide synthesis was performed by the solid-phase method, antimicrobial activity was evaluated by a liquid growth inhibition assay, and conformational studies were performed making use of several spectroscopic techniques: CD, fluorescence and EPR. [TOAC(1)]-Gm; [TOAC(1), Ser(2,6,11,15)]-Gm; [Trp(7)]-Gm; [Ser(2,6,11,15), Trp(7)]-Gm; [Trp(9)]-Gm; and [Ser(2,6,11,15), Trp(9)]-Gm were synthesized and tested. The results indicated that incorporation of TOAC or Trp caused no significant reduction of antimicrobial activity; the cyclic analogues presented a beta-hairpin conformation similar to that of Gm. All analogues interacted with negatively charged SDS both above and below the detergent's critical micellar concentration (cmc). In contrast, while Gm and [TOAC(1)]-Gm required higher LPC concentrations to bind to micelles of this zwitterionic detergent, the cyclic Trp derivatives and the linear derivatives did not seem to interact with this membrane-mimetic system. These data corroborate previous results that suggest that electrostatic interactions with the lipid bilayer of microorganisms play an important role in the mechanism of action of gomesin. Moreover, the results show that hydrophobic interactions also contribute to membrane binding of this antimicrobial peptide. 相似文献
11.
Luis G.M. Moraes Renata F.F. Vieira M. Terêsa M. Miranda Sirlei Daffre 《生物化学与生物物理学报:生物膜》2007,1768(1):52-58
The aim of this work was to examine the bioactivity and the conformational behavior of some gomesin (Gm) analogues in different environments that mimic the biological membrane/water interface. Thus, manual peptide synthesis was performed by the solid-phase method, antimicrobial activity was evaluated by a liquid growth inhibition assay, and conformational studies were performed making use of several spectroscopic techniques: CD, fluorescence and EPR. [TOAC1]-Gm; [TOAC1, Ser2,6,11,15]-Gm; [Trp7]-Gm; [Ser2,6,11,15, Trp7]-Gm; [Trp9]-Gm; and [Ser2,6,11,15, Trp9]-Gm were synthesized and tested. The results indicated that incorporation of TOAC or Trp caused no significant reduction of antimicrobial activity; the cyclic analogues presented a β-hairpin conformation similar to that of Gm. All analogues interacted with negatively charged SDS both above and below the detergent's critical micellar concentration (cmc). In contrast, while Gm and [TOAC1]-Gm required higher LPC concentrations to bind to micelles of this zwitterionic detergent, the cyclic Trp derivatives and the linear derivatives did not seem to interact with this membrane-mimetic system. These data corroborate previous results that suggest that electrostatic interactions with the lipid bilayer of microorganisms play an important role in the mechanism of action of gomesin. Moreover, the results show that hydrophobic interactions also contribute to membrane binding of this antimicrobial peptide. 相似文献
12.
The conformations of [Arg8]vasopressin (AVP) analogues substituted at positions 2 and 3 with N-methylphenylalanine (MePhe) enantiomers were earlier investigated by using nuclear magnetic resonance (NMR) spectroscopy in aqueous solution. A comparison of the results obtained in H2O/D2O (9:1) and DMSO-d6 has shown the structures in the first solution to be more flexible than those in DMSO-d6. This is manifested by a higher percentage of minor conformations in H2O/D2O. The largest differences between the NMR spectra in both solvents were noticed for [MePhe2, D-MePhe3]AVP (II) and [D-Cys1,MePhe2,D-MePhe3]AVP (III). Namely, in the ROESY spectra in aqueous solution, the cis/trans isomerization between MePhe2-DMePhe3 and D-Cys1-MePhe2 for II and III, respectively, is observed, while in DMSO-d6, the appropriate cross peaks indicate isomerization across the Cys6-Pro7 peptide bond. In the case of the remaining peptides, the position of cis/trans isomerization is the same in aqueous solution and in dimethyl sulfoxide. [D-MePhe2,MePhe3]AVP (V) displays low antiuterotonic and antipressor activities, while [D-MePhe2,)]AVP (IV) is a weak but selective blocker of oxytocin (OT) receptors in the uterus. The former shows similar conformational preferences as another antagonist of V1a and OT receptors-namely, [Acc2,D-Arg8]VP (Acc: 1-aminocyclohexane-1-carboxylic acid)-investigated by us. In the case of IV, the cis peptide bond between residues at positions 2 and 3 might be the reason for selectivity. 相似文献
13.
Tschamber T Adam S Matsuya Y Masuda S Ohsawa N Maruyama S Kamoshita K Nemoto H Eustache J 《Bioorganic & medicinal chemistry letters》2007,17(18):5101-5106
4 OSW-1 analogues featuring modified carbohydrate moieties were prepared. The purpose of these modifications was to assess the importance of certain chemical functions with respect to biological activity. The synthesis and biological activity of the target molecules are shown. 相似文献
14.
Preliminary results for the synthesis of two new adenophostin analogues incorporating 3″- and 4″-methylenecarboxylate surrogate groups are presented. The synthesis involves the preparation of 3″- and 4″-methylenecarboxylate glucose derivatives by a radical allylation—oxidative cleavage approach, their conversion into thioglycoside precursors, and stereoselective glycosylation of a suitable adenosine derivative. The glycosylations proceeded with excellent stereoselectivity, only the α product was detected, and in good yields. 相似文献
15.
16.
Joanna Malicka Magorzata Groth Cezary Czaplewski Wiesaw Wiczk Adam Liwo 《Biopolymers》2002,63(4):217-231
The conformation of a series of cyclic enkephalin analogues of a general formula X(1)-cyclo[Y(2)-Z(3)-Nal(4)-Leu(5)] (Nal: beta-(2-naphthyl)alanine), where X = Tyr, Phe, or Phe(NO(2)), Y = D-Dab or L-Dab (Dab: 2,4-diaminobutyric acid), and Z = D-Pro or L-Pro, was studied by means of NMR spectroscopy and theoretical conformational analysis with the Empirical Conformational Energy Program for Peptides and Proteins force field plus solvation. The NMR measurements were performed in dimethyl sulfoxide solution. The nuclear Overhauser effect intensities and coupling constants were used to compute the statistical weights of the conformations of the ensemble generated in global conformational searches. The purpose of this study was to determine whether introducing the D- or L-proline residue in position 3 can produce peptides with both rigid backbone and significant separation of the pharmacophore groups in position 1 and 4 (as required for high affinity for the mu-type opioid receptors). It was found that the analogues with D-Dab in position 2 and D-Pro in position 3 possess a stable type II' beta-turn at positions 3 and 4, which rigidifies the cyclic backbone; this finding was confirmed by independent measurements of the temperature coefficients of the amide protons, which indicated very significant screening of the Leu(5) amide proton from the solvent. However, these analogues were found to possess a short interchromophore distance. The analogues containing both Dab and Pro in the L-configuration are characterized by a larger interchromophore distance; however, they do not possess a stable beta-turn and have therefore a higher conformational flexibility. The modifications proposed in this work are therefore not likely to lead to enkephalin analogues with a high affinity for the mu-receptors. 相似文献
17.
Previous studies have indicated that the methylvalerate subunit of bleomycin (BLM) plays an important role in facilitating DNA cleavage by BLM and deglycoBLM. Eleven methylvalerate analogues have been synthesized and incorporated into deglycoBLM congeners by the use of solid-phase synthesis. The effect of the valerate moiety in the deglycoBLM analogues has been studied by comparison with the parent deglycoBLM A(5) using supercoiled DNA relaxation and sequence-selective DNA cleavage assays. All of the deglycoBLM analogues were found to effect the relaxation of the plasmid DNA. Those analogues having aromatic C4-substituents exhibited cleavage efficiency comparable to that of deglycoBLM A(5). Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage. 相似文献
18.
19.
Colombo D Ronchetti F Scala A Toma L Tokuda H Nishino H 《Bioorganic & medicinal chemistry》2003,11(6):909-912
Glycoglycerolipid analogues lacking the glycerol backbone were prepared through a lipase catalyzed transesterification of beta-D-galactosylethylene glycol. The inhibitory effect of the resultant isomeric hexanoates at the primary alcoholic positions, beta-D-galactosylethylene glycol itself and nonyl beta-D-galactopyranoside, was tested on Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells promoted by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), as a primary screening test for inhibitors of tumor promotion. All the compounds assayed were found to be less active than the reference 2-O-beta-D-galactopyranosylglycerol derivatives, of which they are simplified models, indicating that the anti-tumor-promoting activity is very closely related to the presence of a free hydroxymethylene group on the glycerol-like aglycone moiety. 相似文献
20.
Summary Conformationally restricted cyclic analogues of angiotensin II (ANG II), Asp1-Arg2-Val3-Tyr4-Val5-His6-Pro7-Phe8, with a link between positions 3 and 5 have considerable biological activity. It is proposed that the spatial arrangement of the pharmacophore groups of Tyr4, His6 and Phe8 side chains and the C-terminal carboxyl group in ANG II and active analogues is similar. Conformational analysis of ANG II and two cyclic analogues c[Sar1, Lys3,Glu5]ANG II and c[Sar1,Hcy3,Mpt5]ANG II was performed, and a geometrical comparison of the low-energy conformations of these compounds allowed one to propose a model of receptor-bound conformation in terms of the spatial arrangement of the pharmacophore groups. This model is characterised by the close spatial location of the His6-Phe8 side chains and the Tyr4 C-terminal carboxyl group and is stabilised by the electrostatic interaction of Arg2 and the C-terminal carboxyl group.Abbreviations ANG II
angiotensin II
- Hcy
homocysteine
- Mpt
trans-4-mercaptoproline 相似文献