A new approach to the therapy of diseases induced by Mycobacteria invasion.
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Anti-Bacterial Agents↗
Biomedical subjects
Z Wieczorek
Publications and source records attributed to Z Wieczorek.
Synthesis, conformation, and immunosuppressive activity of CLX and its analogues.
The CLX peptide isolated from flax seed has a sequence cyclo-(PPFFILLX), where X is a nonproteinaceous amino acid residue, (2S,4R) 4-amine-N-methylproline. Picur, B.; Lisowski, M.; Siemion, I.Z. Letters Pept Sci 1998, 5, 183-187. The structure of X strongly suggests that this natural amino acid plays a role of the dipeptide moiety with a nonplanar cis peptidomimetic bond. The X residue contains two asymmetrical carbons and thus can appear in four configurations: (2S,4R), (2S,4S), (2R,4S), and (2R,4R). All four diastereoisomers of X were synthesized and characterized as trifluoroacetates of 4-phtalimido-N-methylproline benzylamides. Their full physicochemical characteristics are presented in this article. The synthesis of linear and cyclic analogues of CLX containing all four possible diastereoisomers of X was performed. Additionally, analogues with gamma-aminobutyric acid (GABA) and glycyl-N-methyl-glycine dipeptide [G(Me)G] substituted for X were synthesized. The obtained peptides were purified using HPLC, examined by ESI/MS, and then studied by CD spectroscopy. They were also tested for immunosuppressive activity (PFC in vitro). All of them revealed diverse immunosuppressive activity, however, lower than that of cyclolinopeptide A (CLA) Wieczorek, Z.; Bengtsson, B.; Trojnar, J.; Siemion, I.Z. Peptide Res 1991, 4, 275-283. and cyclosporine A (CsA). Ellis, G.P.; West, G.B. Progress Med Chem 1988, 25, 1-33. The structure of CLX with (2S,4R) 4-amino-N-methylproline was determined by 2-D NMR methods. All amide bonds are in the trans configuration. The cis peptidomimetic group delta-CH(2)-N(CH(3))- is exposed to the outside of the CLX molecule. The peptide contains two loops similar to beta-turns of type IV. Chou, P.Y.; Fasman, G.D. J Mol Biol 1977, 115, 136-715 and has the extended shape flanked by F3 and L7 residues with significant side chain flexibility.
Circular Dichroism↗
Immunosuppressory activity of the cyclodimeric peptide with RGD-sequences.
Our previous studies showed that the nonapeptide fragment of HLA-DQ of the sequence H-Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr-OH, located in the beta164-172 loop, strongly suppresses the humoral and cellular immune responses, while its shorter analogs, H-Arg-Gly-Asp-Val-OH, H-Arg-Gly-Asp-Val-Tyr-OH and H-Gln-Arg-Gly-Asp-Val-Tyr-OH show only a weak stimulatory activity in respect to the humoral immunological response. These fragments contain the Arg-Gly-Asp (RGD) sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog H-Cys-Arg-Gly-Asp-Val-Tyr-Cys-OH with restricted conformation, which strongly suppresses the immune response and selectively inhibits the alphavbeta3 integrin, suggesting that the mechanism of the immunosuppressory action of the peptide is associated with inhibition of the integrin. In this paper we present the design and synthesis of the cyclodimeric peptide, Arg-Gly-Asp-Arg-Gly-Asp, which is also known as a selective alphavbeta3 inhibitor. The synthesized peptide strongly suppresses both the humoral and cellular immune response. The results support our hypothesis that the immunomodulatory activity of HLA-DQ fragments may be connected with their interactions with some particular integrins on the cell surface.
Amino Acid Sequence↗
Design, synthesis and biological evaluation of a new bridged immunosuppressor.
A bridged peptide with the sequence: H-Thr-Pro-Gln-Arg-Gly-Asp-Val-gamma-Abu-Asn-Asp-Gln-Glu-Glu-Thr-Thr-Gly-Val-Val-Ser-Thr-Pro-Leu-Ile-Arg-Asn-Gly-OH was designed to mimic the discontinuous epitope of the HLA-DQ molecule that might interact with CD4. The bridged peptide revealed distinct suppressory effect in the humoral immune response. This result supports our suggestion that the 164-172 region of the HLA-DQ molecule may enhance its interactions with coreceptors, possibly with CD4.
Animals↗
The "two-headed" peptide inhibitors of interleukin-1 action.
Two peptide fragments of IL-1 family proteins, ITGSE and VTKFYF compete with IL-1 for the cellular receptor. We synthesized a series of peptides composed of the sequences ITGSE and VTKFYK bound directly to each other or connected by such linkers as (Gly)(n), L- and D-Pro residues, Glu and Lys residues (with peptide bond formed by main amino and carboxy groups or by side chain groups), and beta-alanine and its homologues. Peptide IX with a gamma-Glu linker was the most potent inhibitor of IL-1 action. It was twice as potent as both of the peptides indicated.
Animals↗
New conformationally restricted analog of the immunosuppressory mini-domain of HLA-DQ and its biological properties.
Our previous studies revealed that the nonapeptide fragment of HLA-DQ located in the beta 164-172 loop of the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence suppresses the immune humoral and cellular responses [30]. Based on the crystal structure of HLA-class II molecules we designed and synthesized a cyclic analog with restricted conformation, cyclo(Suc-Thr-Pro-Gln-Arg-Gly-Asp-Val-Lys)-Thr-OH (Suc = succinyl) by reacting a Lys side chain with a succinylated N-terminus. The cyclization product more potently suppresses the cellular immune response than its linear counterparts and is efficiently cleaved by trypsin. The results indicate that the beta 164-172 loop may serve as a functional epitope on the HLA class II surface for intermolecular binding.
Amino Acid Sequence↗
[Retrospective evaluation of the knee function after partial resection of the fat body of the knee].
A series of 64 male patients aged 16-58 years (average 37 years) underwent in the years 1992-1997 a partial resection of the Hoffa pad. The results of this procedure were evaluated. The patients underwent surgery for diagnosed tear of the medial meniscus. At arthrotomy the meniscus was found to be intact and the only visible pathology appeared to be hypertrophic Hoffa pad impinging between the articular surfaces of the joint. The authors attempted to answer the following question: is partial resection of the fat body of the knee a therapeutic procedure or an excuse to justify surgery? The results presented in this paper confirm the therapeutic usefulness of this procedure.
Adipose Tissue↗
Immunosuppressory mini-regions of HLA-DP and HLA-DR.
Our previous studies showed, that the,TPQRGDVYT, QRGDVYT and RGDVYT fragments, located in the beta164-172 loop of HLA-DQ, strongly suppress the humoral and cellular immune response, while their shorter analogs, RGDV, RGDVY, and QRGDVY, show only weak stimulatory activity in respect to humoral immunological response. The fragments contain the RGDVY sequence that is analogous to thymopentin (pentapeptide RKDVY, an immune system activator) as well as the RGD sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog C*RGDVYC* (where C* indicates Cys participating in disulfide bridge) with restricted conformation, which strongly suppresses both humoral and cellular immune response. In the present study we synthesized and tested the immunological properties of the linear and cyclic HLA-DP and HLA-DR counterparts of all the above HLA-DQ fragments. Although the results show that the linear HLA-DP fragments possess moderate immunosuppressory potency, their conformationally restricted analog, C*QGDVYC*C shows a considerable suppression of both humoral and cellular immune response. The nonapeptide fragment of HLA-DR, VPRSGEVYT and particularly its cyclic analog C*SGEVYC*, are strong suppressors of the humoral response.
Amino Acid Sequence↗
Length of the peptide chain influences the immunomodulatory activity of peptides related to p53 protein.
We have shown that the thymopoietin-like octapeptides derived from DNA-binding domain of p53 protein and of its mutated forms differ in their immunomodulatory properties. A strong increase of immunostimulative activity was observed for GMNRSPIL (mutated protein) in comparison with GMNRRPIL (wild-type of p53 protein) peptide. Here the elongated sequences of respective protein fragments were synthesized and investigated by plaque forming cells and delayed type hypersensitivity tests. The change of immunomodulatory activity toward immunosuppression was observed: NSSC(Acm)MGGMNRRPILTIITLE (1, wild-type) was inactive in both tests, and the C(Acm)MGGMNRSPILTIITLE (II) and YMC(Acm)NSSC(Acm)MGGMNRSPILTIITLE (III) (mutated p53 protein fragments) peptides produced immunosuppression in plaque forming cells as well as in delayed type hypersensitivity tests.
Adjuvants, Immunologic↗
Synthesis and immunological activity of new 5-amino-3-methyl 4-amido and 4-ureilene isoxazole derivatives.
5-Amino-3-methylisoxazole-4-carboxylic acid amides and ureilenes have been synthesized from 5-amino-3-methylisoxazole-4-carbonyl azide. The compounds were investigated for potential immunotropic activity in several immunological tests. The most interesting suppressory activities in the humoral and cellular immune response were compared to activities of analogous compounds previously described as immunostimulatory.
Adjuvants, Immunologic↗
Cyclolinopeptides and their analogs--a new family of peptide immunosuppressants affecting the calcineurin system.
The results of the investigation of immunosuppressive activity of cyclolinopeptide A (CLA--cyclic hydrophobic nonapeptide present in the linseeds) and its analogs are discussed. The results obtained for other natural cyclic peptides showing structural similarities with CLA (antamanide, cycloamanides, hymenistatin, hymenamides) are also reviewed. It results from these investigations that the molecular mechanism of the CLA action is the same as that of cyclosporin A and FK-506 compound, i.e. it consists in formation of the complex with cyclophilin and inhibition--in this form--of the phosphatase activity of calcineurin. The results also suggest that the immunosuppressive activity of these compounds resides in their--Pro-Xxx-Phe- fragment, where Xxx is a hydrophobic (e.g. Leu, Val) or aromatic amino acid residue.
Amino Acid Sequence↗
A fluorescence spectroscopic study on the binding of mRNA 5'-cap-analogs to human translation initiation factor eIF4E: a critical evaluation of the sources of error.
Equilibrium constants for the association of human protein translation initiation factor eIF4E with two mRNA 5'-cap analogs, namely 7-methylguanosine 5'-triphosphate and P1-(7-methylguanosine-5') P3-(guanosine-5') triphosphate, and with guanosine 5'-monophosphate have been redetermined by the fluorescence quenching method taking the inner filter effect of the cap-analog into account. It has been shown that neglecting the latter correction may lead to either underestimation or overestimation of the association constant obtained by applying the Eadie-Hofstee plot: the reasonably firm binding of 7-methylated cap-analogs becomes underestimated, while the weak binding of non-methylated nucleotides becomes overestimated.
Binding Sites↗
Anti-IL-1 activity of peptide fragments of IL-1 family proteins.
A series of peptides containing retro-tuftsin- and tuftsin-like motifs from IL-1 proteins inhibits IL-1-induced IL-2 production and reduces the humoral immune response, thus supporting our hypothesis that tuftsin (Thr-Lys-Pro-Arg)-IL-1 competition depends on the presence of such motifs in IL-1 proteins. Some other peptides from regions of IL-1 responsible for receptor binding were also active, with peptide Ile-Thr-Gly-Ser-Glu (III) from IL-1alpha (residues 98-102), not only strongly affecting IL-2 production, but also suppressing the immune response; the analogue of hexapeptide Val-Thr-Lys-Phe-Tyr-Phe from the C-terminal part of IL-lra, with Lys replaced by Asp, was as efficient as Val-Thr-Lys-Phe-Tyr-Phe with respect to IL-1 competition.
Amino Acid Sequence↗
Peptides related to FKBP 39-45 loop possess immunostimulative potency.
Taking into account the sequential homology existing between thymopoietin II, the DNA-binding domain of p53 protein and FKBP (FK-506 binding protein), a series of fragments of human and bovine FKBP containing a fragment Ser39-Pro45 were synthesized. In the humoral in vitro test all the peptides act as stimulators. Whereas in the in vivo test peptides derived from bovine FKBP show an immunostimulative and those from human FKBP an immunosuppressive activity. However, after blocking the Asp residue by a Bzl group the peptide V appears to be an immunostimulator. The data obtained suggest that these peptides can influence the immune system by blocking the FKBP receptor.
Adjuvants, Immunologic↗
Fluorescence and NMR studies of intramolecular stacking of mRNA cap-analogues.
Intramolecular stacking of a series of new synthesized dinucleotide mRNA cap analogues has been investigated in aqueous buffers by means of fluorescence and 1H-NMR at various pH and temperatures, and compared with that for 7-methylguanosine(5')ppp(5')guanosine (m7GpppG), as well as its hypermethylated derivative m(3)2,2,7GpppG. Thermodynamic parameters for intramolecular self-association stabilized by stacking were established by temperature-dependent fluorescence quenching, taking into account collisional deactivation of the excited states. Relative orientations of the stacked bases in the cap analogues were determined with the aid of a program GEOSHIFT (Stolarski et al., Biochim. Biophys. Acta (1996) 1293, 97), based on ring-current anisotropy. 1D-soft-TOCSY experiments were applied to extract the exact values of vicinal coupling constants, and hence to resolve solution conformation of the cap molecules. Stacking interaction has been discussed in detail in terms of the cap structural features, e.g., types of bases and length of the 5',5'-phosphate bridges, and regarding the interactions stabilizing intramolecular stacking.
Hydrogen-Ion Concentration↗
Synthesis and structure elucidation of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides and their immunological activity.
A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4. The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response (4d), humoral immune response (4a), or cellular immune response (4c). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.
Adjuvants, Immunologic↗
Sulfonated analogues of cyclolinopeptide A. Synthesis, immunosuppressive activity and CD studies.
Linear and cyclic analogues of cyclolinopeptide A (CLA) in which one or both phenylalanine residues in fragment Pro6-Pro7-Phe8-Phe9 were substituted by their sulfonated derivatives have been synthesized by SPPS method and cyclization with the BOP reagent. The peptides were examined for their immunosuppressive activity in the humoral and cellular immune response by PFC and DTH tests. All of the analogues retain some immunosuppressive activity of native CLA. Their CD spectra confirm that the optical activity of aromatic residues in CLA depends on their position in the peptide chain. Only the residue in position 8 seems to be optically active. CD spectrum of the cyclic analogue modified in position 9 is very similar to that of native CLA which correlates with its high biological activity. The chiroptical properties of the p-sulfonated Phe-residue are established.
Amino Acid Sequence↗
Immunomodulatory activity of G-actin fragments containing a thymopentin-like sequence.
A discontinuous thymopoietin-like motif, composed of the fragments 97-111 and 277-307 of the molecule, as well as of residues Arg178 and Asn163 of G-actin was found. It was established that G-actin has an immunosuppressive activity regarding the humoral immune response. This activity is probably connected to the thymopentin-like sequence RKDLY, which is present in the 277-307 fragment of G-actin. The immunomodulatory activity of a series of peptide-partial sequences of G-actin was tested using plaque-forming cells (PFC) and delayed type hypersensitivity (DTH) tests. The investigated series consisted of five peptides: RKDLY (I), RKDLYANT (II), DVDIRKDLY (III), DVDIR (NO2)KDLY (IV), DVDIRKDLYANT (V). The peptides have the immunosuppressive activity regarding the humoral and cellular immune response.
Actins↗