The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Timur I. Abdullin - One of the best experts on this subject based on the ideXlab platform.
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Effect of triphenylphosphonium moiety on spatial structure and biointeractions of stereochemical variants of YRFK motif
European Biophysics Journal, 2019Co-Authors: Ruslan Garifullin, Dmitriy S. Blokhin, Rezeda A. Akhmadishina, Natalia V. Petrova, Alexandra M. Kusova, Vladimir V. Klochkov, Timur I. AbdullinAbstract:Chemical modification of therapeutic peptides is an important approach to improving their physicochemical and pharmacokinetic properties. The triphenylphosphonium (TPP) cation has proved to be a powerful modifier; however, its effects on peptide structure and activity remain uncharacterized. In this study, cytoprotective Tetrapeptides based on the YRFK opioid motif with l - or d -Arg residues were linked to (triphenylphosphonio)carboxylic acids with ethylene and pentylene spacers (TPP-3 and TPP-6 groups, respectively). The three-dimensional structure of the oligopeptides was analyzed by NMR spectroscopy, computational methods and circular dichroism (CD). A more compact and bent structure with segregated aromatic groups was revealed for the d -arginine-containing Tetrapeptide and its TPP-6 derivative. The TPP moiety caused structure-organizing effect on the Tetrapeptides, resulting in transition from random coil to β-sheet structures, and decreased the peptide backbone flexibility up to ten times. The TPP-3-modified oligopeptide with the lowest RMSD value (ca. 0.05 Å) was characterized by intrapeptide hydrophobic interactions between the TPP and side groups of Tyr and Phe residues accompanied by strong CD induction. The TPP-6-modified oligopeptides showed enhanced ability to form intermolecular associates and disturb liposomal membranes. The relationship between the spatial structure of the oligopeptides and some of their biologically relevant interactions were additionally revealed and are discussed.
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Presentation_1.pdf
2018Co-Authors: Rezeda A. Akhmadishina, Ruslan Garifullin, Natalia V. Petrova, Marat I. Kamalov, Timur I. AbdullinAbstract:Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant Tetrapeptides based on the model opioid YRFK motif was studied. Two Tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the Tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.
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Triphenylphosphonium Moiety Modulates Proteolytic Stability and Potentiates Neuroprotective Activity of Antioxidant Tetrapeptides in Vitro
Frontiers Media S.A., 2018Co-Authors: Rezeda A. Akhmadishina, Ruslan Garifullin, Natalia V. Petrova, Marat I. Kamalov, Timur I. AbdullinAbstract:Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant Tetrapeptides based on the model opioid YRFK motif was studied. Two Tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the Tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties
Lila M. Gierasch - One of the best experts on this subject based on the ideXlab platform.
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Nonfarnesylated Tetrapeptide inhibitors of protein farnesyltransferase.
The Journal of biological chemistry, 1991Co-Authors: Joseph L. Goldstein, Sarah J. Stradley, Yuval Reiss, Michael S. Brown, Lila M. GieraschAbstract:The protein farnesyltransferase from rat brain was previously shown to be inhibited competitively by Tetrapeptides that conform to the consensus Cys-A1-A2-X, where A1 and A2 are aliphatic amino acids and X is methionine, serine, or phenylalanine. In the current studies we use a thin layer chromatography assay to show that most of these Tetrapeptides are themselves farnesylated by the purified enzyme. Two classes of Tetrapeptides are not farnesylated and therefore act as true inhibitors: 1) those that contain an aromatic residue at the A2 position and 2) those that contain penicillamine (beta,beta-dimethylcysteine) in place of cysteine. The most potent of these pure inhibitors was Cys-Val-Phe-Met, which inhibited farnesyltransferase activity by 50% at less than 0.1 microM. These data indicate that the inclusion of bulky aromatic or methyl residues in a Tetrapeptide can abolish prenyl group transfer without blocking binding to the enzyme. This information should be useful in the design of peptides or peptidomimetics that inhibit farnesylation and thus block the action of p21ras proteins in animal cells.
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Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Yuval Reiss, Sarah J. Stradley, Lila M. Gierasch, Michael S. Brown, Joseph L. GoldsteinAbstract:Abstract We tested 42 Tetrapeptides for their ability to bind to the rat brain p21ras protein farnesyltransferase as estimated by their ability to compete with p21Ha-ras in a farnesyltransfer assay. Peptides with the highest affinity had the structure Cys-A1-A2-X, where positions A1 and A2 are occupied by aliphatic amino acids and position X is occupied by a COOH-terminal methionine, serine, or phenylalanine. Charged residues reduced affinity slightly at the A1 position and much more drastically at the A2 and X positions. Effective inhibitors included Tetrapeptides corresponding to the COOH termini of all animal cell proteins known to be farnesylated. In contrast, the Tetrapeptide Cys-Ala-Ile-Leu (CAIL), which corresponds to the COOH termini of several neural guanine nucleotide binding (G) protein gamma subunits, did not compete in the farnesyl-transfer assay. Inasmuch as several of these proteins are geranylgeranylated, the data suggest that the two isoprenes (farnesyl and geranylgeranyl) are transferred by different enzymes. A biotinylated heptapeptide corresponding to the COOH terminus of p21Ki-rasB was farnesylated, suggesting that at least some of the peptides serve as substrates for the transferase. The data are consistent with a model in which a hydrophobic pocket in the protein farnesyltransferase recognizes Tetrapeptides through interactions with the cysteine and the last two amino acids.
Joseph L. Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Tetrapeptide inhibitors of protein farnesyltransferase : amino-terminal substitution in phenylalanine-containing Tetrapeptides restores farnesylation
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Michael S. Brown, Joseph L. Goldstein, Kenneth J. Paris, John Burnier, James C. MarstersAbstract:Abstract Protein farnesyltransferase from rat brain transfers farnesyl residues to cysteine residues in Tetrapeptides that conform to the sequence CA1A2X, where C is cysteine, A1 and A2 are aliphatic amino acids, and X is methionine or serine. When the A2 residue is aromatic [e.g., phenylalanine as in Cys-Val-Phe-Met (CVFM)], the Tetrapeptide continues to bind to the enzyme, but it can no longer accept a farnesyl group, and it becomes a pure inhibitor. The current studies show that this resistance to farnesylation also requires a positive charge on the cysteine amino group. Derivatization of this group with acetyl, octanoyl, or cholic acid residues or extension of the peptide with an additional amino acid restores the ability of phenylalanine-containing peptides to accept a farnesyl residue. The same result was obtained when the amino group of cysteine was deleted (mercaptopropionyl-VFM). These data suggest that the positive change on the cysteine amino group acts in concert with an aromatic residue in the A2 position to render peptides resistant to farnesylation by the rat brain enzyme.
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Nonfarnesylated Tetrapeptide inhibitors of protein farnesyltransferase.
The Journal of biological chemistry, 1991Co-Authors: Joseph L. Goldstein, Sarah J. Stradley, Yuval Reiss, Michael S. Brown, Lila M. GieraschAbstract:The protein farnesyltransferase from rat brain was previously shown to be inhibited competitively by Tetrapeptides that conform to the consensus Cys-A1-A2-X, where A1 and A2 are aliphatic amino acids and X is methionine, serine, or phenylalanine. In the current studies we use a thin layer chromatography assay to show that most of these Tetrapeptides are themselves farnesylated by the purified enzyme. Two classes of Tetrapeptides are not farnesylated and therefore act as true inhibitors: 1) those that contain an aromatic residue at the A2 position and 2) those that contain penicillamine (beta,beta-dimethylcysteine) in place of cysteine. The most potent of these pure inhibitors was Cys-Val-Phe-Met, which inhibited farnesyltransferase activity by 50% at less than 0.1 microM. These data indicate that the inclusion of bulky aromatic or methyl residues in a Tetrapeptide can abolish prenyl group transfer without blocking binding to the enzyme. This information should be useful in the design of peptides or peptidomimetics that inhibit farnesylation and thus block the action of p21ras proteins in animal cells.
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Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Yuval Reiss, Sarah J. Stradley, Lila M. Gierasch, Michael S. Brown, Joseph L. GoldsteinAbstract:Abstract We tested 42 Tetrapeptides for their ability to bind to the rat brain p21ras protein farnesyltransferase as estimated by their ability to compete with p21Ha-ras in a farnesyltransfer assay. Peptides with the highest affinity had the structure Cys-A1-A2-X, where positions A1 and A2 are occupied by aliphatic amino acids and position X is occupied by a COOH-terminal methionine, serine, or phenylalanine. Charged residues reduced affinity slightly at the A1 position and much more drastically at the A2 and X positions. Effective inhibitors included Tetrapeptides corresponding to the COOH termini of all animal cell proteins known to be farnesylated. In contrast, the Tetrapeptide Cys-Ala-Ile-Leu (CAIL), which corresponds to the COOH termini of several neural guanine nucleotide binding (G) protein gamma subunits, did not compete in the farnesyl-transfer assay. Inasmuch as several of these proteins are geranylgeranylated, the data suggest that the two isoprenes (farnesyl and geranylgeranyl) are transferred by different enzymes. A biotinylated heptapeptide corresponding to the COOH terminus of p21Ki-rasB was farnesylated, suggesting that at least some of the peptides serve as substrates for the transferase. The data are consistent with a model in which a hydrophobic pocket in the protein farnesyltransferase recognizes Tetrapeptides through interactions with the cysteine and the last two amino acids.
Michael S. Brown - One of the best experts on this subject based on the ideXlab platform.
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Tetrapeptide inhibitors of protein farnesyltransferase : amino-terminal substitution in phenylalanine-containing Tetrapeptides restores farnesylation
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Michael S. Brown, Joseph L. Goldstein, Kenneth J. Paris, John Burnier, James C. MarstersAbstract:Abstract Protein farnesyltransferase from rat brain transfers farnesyl residues to cysteine residues in Tetrapeptides that conform to the sequence CA1A2X, where C is cysteine, A1 and A2 are aliphatic amino acids, and X is methionine or serine. When the A2 residue is aromatic [e.g., phenylalanine as in Cys-Val-Phe-Met (CVFM)], the Tetrapeptide continues to bind to the enzyme, but it can no longer accept a farnesyl group, and it becomes a pure inhibitor. The current studies show that this resistance to farnesylation also requires a positive charge on the cysteine amino group. Derivatization of this group with acetyl, octanoyl, or cholic acid residues or extension of the peptide with an additional amino acid restores the ability of phenylalanine-containing peptides to accept a farnesyl residue. The same result was obtained when the amino group of cysteine was deleted (mercaptopropionyl-VFM). These data suggest that the positive change on the cysteine amino group acts in concert with an aromatic residue in the A2 position to render peptides resistant to farnesylation by the rat brain enzyme.
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Nonfarnesylated Tetrapeptide inhibitors of protein farnesyltransferase.
The Journal of biological chemistry, 1991Co-Authors: Joseph L. Goldstein, Sarah J. Stradley, Yuval Reiss, Michael S. Brown, Lila M. GieraschAbstract:The protein farnesyltransferase from rat brain was previously shown to be inhibited competitively by Tetrapeptides that conform to the consensus Cys-A1-A2-X, where A1 and A2 are aliphatic amino acids and X is methionine, serine, or phenylalanine. In the current studies we use a thin layer chromatography assay to show that most of these Tetrapeptides are themselves farnesylated by the purified enzyme. Two classes of Tetrapeptides are not farnesylated and therefore act as true inhibitors: 1) those that contain an aromatic residue at the A2 position and 2) those that contain penicillamine (beta,beta-dimethylcysteine) in place of cysteine. The most potent of these pure inhibitors was Cys-Val-Phe-Met, which inhibited farnesyltransferase activity by 50% at less than 0.1 microM. These data indicate that the inclusion of bulky aromatic or methyl residues in a Tetrapeptide can abolish prenyl group transfer without blocking binding to the enzyme. This information should be useful in the design of peptides or peptidomimetics that inhibit farnesylation and thus block the action of p21ras proteins in animal cells.
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Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Yuval Reiss, Sarah J. Stradley, Lila M. Gierasch, Michael S. Brown, Joseph L. GoldsteinAbstract:Abstract We tested 42 Tetrapeptides for their ability to bind to the rat brain p21ras protein farnesyltransferase as estimated by their ability to compete with p21Ha-ras in a farnesyltransfer assay. Peptides with the highest affinity had the structure Cys-A1-A2-X, where positions A1 and A2 are occupied by aliphatic amino acids and position X is occupied by a COOH-terminal methionine, serine, or phenylalanine. Charged residues reduced affinity slightly at the A1 position and much more drastically at the A2 and X positions. Effective inhibitors included Tetrapeptides corresponding to the COOH termini of all animal cell proteins known to be farnesylated. In contrast, the Tetrapeptide Cys-Ala-Ile-Leu (CAIL), which corresponds to the COOH termini of several neural guanine nucleotide binding (G) protein gamma subunits, did not compete in the farnesyl-transfer assay. Inasmuch as several of these proteins are geranylgeranylated, the data suggest that the two isoprenes (farnesyl and geranylgeranyl) are transferred by different enzymes. A biotinylated heptapeptide corresponding to the COOH terminus of p21Ki-rasB was farnesylated, suggesting that at least some of the peptides serve as substrates for the transferase. The data are consistent with a model in which a hydrophobic pocket in the protein farnesyltransferase recognizes Tetrapeptides through interactions with the cysteine and the last two amino acids.
Ruslan Garifullin - One of the best experts on this subject based on the ideXlab platform.
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Effect of triphenylphosphonium moiety on spatial structure and biointeractions of stereochemical variants of YRFK motif
European Biophysics Journal, 2019Co-Authors: Ruslan Garifullin, Dmitriy S. Blokhin, Rezeda A. Akhmadishina, Natalia V. Petrova, Alexandra M. Kusova, Vladimir V. Klochkov, Timur I. AbdullinAbstract:Chemical modification of therapeutic peptides is an important approach to improving their physicochemical and pharmacokinetic properties. The triphenylphosphonium (TPP) cation has proved to be a powerful modifier; however, its effects on peptide structure and activity remain uncharacterized. In this study, cytoprotective Tetrapeptides based on the YRFK opioid motif with l - or d -Arg residues were linked to (triphenylphosphonio)carboxylic acids with ethylene and pentylene spacers (TPP-3 and TPP-6 groups, respectively). The three-dimensional structure of the oligopeptides was analyzed by NMR spectroscopy, computational methods and circular dichroism (CD). A more compact and bent structure with segregated aromatic groups was revealed for the d -arginine-containing Tetrapeptide and its TPP-6 derivative. The TPP moiety caused structure-organizing effect on the Tetrapeptides, resulting in transition from random coil to β-sheet structures, and decreased the peptide backbone flexibility up to ten times. The TPP-3-modified oligopeptide with the lowest RMSD value (ca. 0.05 Å) was characterized by intrapeptide hydrophobic interactions between the TPP and side groups of Tyr and Phe residues accompanied by strong CD induction. The TPP-6-modified oligopeptides showed enhanced ability to form intermolecular associates and disturb liposomal membranes. The relationship between the spatial structure of the oligopeptides and some of their biologically relevant interactions were additionally revealed and are discussed.
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Presentation_1.pdf
2018Co-Authors: Rezeda A. Akhmadishina, Ruslan Garifullin, Natalia V. Petrova, Marat I. Kamalov, Timur I. AbdullinAbstract:Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant Tetrapeptides based on the model opioid YRFK motif was studied. Two Tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the Tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.
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Triphenylphosphonium Moiety Modulates Proteolytic Stability and Potentiates Neuroprotective Activity of Antioxidant Tetrapeptides in Vitro
Frontiers Media S.A., 2018Co-Authors: Rezeda A. Akhmadishina, Ruslan Garifullin, Natalia V. Petrova, Marat I. Kamalov, Timur I. AbdullinAbstract:Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant Tetrapeptides based on the model opioid YRFK motif was studied. Two Tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the Tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties
