Peptide synthesis by a combination of solid-phase and solution methods I: A new very acid-labile anchor group for the solid phase synthesis of fully protected fragments

Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P.

doi:10.1016/s0040-4039(00)80405-0

Cited by 175 publications

(41 citation statements)

References 14 publications

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“…The increased quantity of glycopeptide to be prepared required modification of the existing glycopeptide synthetic strategy. Assembly of the peptides proceeded on 1.5 g (loading: 0.33 mmol) of p-alkoxybenzyl alcohol resin [19] (Bachem) until Serl2 was completely incorporated. The amino acids were coupled with a 4-molar excess to the resin for 90 rnin each.…”

Section: Methodsmentioning

confidence: 99%

Enlarged Scale Chemical Synthesis and Range of Activity of Drosocin, an O‐Glycosylated Antibacterial Peptide of Drosophila

Bulet¹,

Ürge²,

Ohresser³

et al. 1996

European Journal of Biochemistry

113

129

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Insects respond to a bacterial challenge by rapidly synthesizing a diverse range of antibacterial and antifungal peptides. One of them, drosocin, a 19-residue proline-rich antibacterial peptide, was isolated from Drosophila. This peptide carries a disaccharide moiety attached to a threonine residue in mid-chain position. The present report describes the enlarged-scale chemical synthesis of drosocin, glycosylated with Gal(~l+3)GalNAc(al+O). We have studied the range of activity of the synthetic glycopeptide, of two truncated glycosylated isoforms, and of the unglycosylated L and D enantiomers. Both isolated and chemically synthesized drosocins carrying the disaccharide display the same antibacterial activity. Using circular dichroic spectroscopy we demonstrated that the 0-linked disaccharidic motif did not affect the backbone conformation of drosocin. The antibacterial activity of the synthetic glycopeptide was directed against gram-negative strains with the exception of the gram-positive bacteria Micrococcus luteus. Deletion of the first five N-terminal residues completely abolished the activity of drosocin. As a first approach to the study of the mode of action of drosocin, we have synthesized a non-glycosylated D enantiomer and, using this molecule, we have shown that drosocin may act on the gram-negative bacteria through a stereospecific target.

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Section: Methodsmentioning

confidence: 99%

Enlarged Scale Chemical Synthesis and Range of Activity of Drosocin, an O‐Glycosylated Antibacterial Peptide of Drosophila

Bulet¹,

Ürge²,

Ohresser³

et al. 1996

European Journal of Biochemistry

113

129

View full text Add to dashboard Cite

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“…-Leu-Leu-resin was prepared on the 2-methoxy-4-alkoxybenzyl alcohol resin (substitution level, 0.45 mmol/g resin) with Fmoc amino acids (22,23). A standard Fmoc peptide synthesis protocol was employed using an automated peptide synthesizer (Advanced ChemTech Act 90).…”

Section: Methodsmentioning

confidence: 99%

Precision Substrate Targeting of Protein Kinases v-Abl and c-Src

Lee

Till

Lawrence

et al. 1995

Journal of Biological Chemistry

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The active site substrate specificities of v-Abl and cSrc are compared and contrasted. Both enzymes catalyze the phosphorylation of a broad assortment of peptide-bound aliphatic and aromatic alcohols, such as achiral and simple straight chain residues. In addition, both protein kinases exhibit a "dual specificity" with respect to the ability to utilize D-and L-configurational isomers as substrates. However, c-Src and v-Abl are extremely inefficient as catalysts for certain structural arrangements, including secondary alcohols and primary alcohols containing large substituents in close proximity to the hydroxyl moiety. In addition to these similarities, these enzymes also display noteworthy differences in catalytic behavior. Whereas c-Src exhibits a modest preference for aromatic versus aliphatic alcohols, v-Abl does not. Most dramatic is the ability of c-Src to utilize short chain alcohols as substrates, an activity virtually absent from the catalytic repertoire of v-Abl. The implications of these observations are 2-fold. First, because both enzymes are able to accommodate a wide variety of structural variants within their respective active site regions, there exists a substantial degree of flexibility with respect to inhibitor design. Second, because these enzymes exhibit disparate active site specificities, it is possible that other tyrosine-specific protein kinases will display unique substrate specificities as well. Consequently, it may ultimately be possible to exploit these differences to generate inhibitors that precisely target specific protein kinases.Protein phosphorylation plays a pivotal role in signaling pathways, which regulate such fundamental processes as cell growth, differentiation, and division (1, 2). Consequently, protein kinase inhibitors that can be precisely directed to specific members of the kinase family could prove to be of decided utility in understanding and controlling these signaling pathways. Much of the effort devoted to the design and construction of agents that are targeted to individual protein kinases has focused on the identification of characteristic substrate sequence specificities. Because most protein kinases utilize short peptides as substrates (3, 4), it may be possible to create inhibitors for specific protein kinases by employing peptides containing appropriate primary sequences. Unfortunately, this approach suffers from the limitation that many kinases exhibit broad overlapping sequence specificities with other family members. One way to overcome this obstacle is to employ additional recognition motifs in conjunction with the specific primary sequence to narrow the range of kinases that are impaired by inhibitory species.We have developed a facile method to rapidly assess the active site substrate specificity of protein kinases (5-11). Although protein kinases will generally phosphorylate only serine, threonine, and/or tyrosine residues in intact protein substrates, we have found that these enzymes will phosphorylate a diverse array of alcohol-containing non-amino ...

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“…The synthesis started with L-lysine with its ␣ amino group protected by a Fmoc group bound to resin beads with an acidlabile super acid-sensitive resin linker (47,48). The ⑀-amine was protected with a Mtt group, which was removed under weakly acidic conditions at the final release (Fig.…”

Section: Isolation Of Individual Molecularmentioning

confidence: 99%

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

Young

Kasmar

Moraski

et al. 2009

Journal of Biological Chemistry

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Mycobacterium tuberculosis survival in cells requires mycobactin siderophores. Recently, the search for lipid antigens presented by the CD1a antigen-presenting protein led to the discovery of a mycobactin-like compound, dideoxymycobactin (DDM). Here we synthesize DDMs using solution phase and solid phase peptide synthesis chemistry. Comparison of synthetic standards to natural mycobacterial mycobactins by nuclear magnetic resonance and mass spectrometry allowed identification of an unexpected ␣-methyl serine unit in natural DDM. This finding further distinguishes these pre-siderophores as foreign compounds distinct from conventional peptides, and we provide evidence that this chemical variation influences the T cell response. One synthetic DDM recapitulated natural structures and potently stimulated T cells, making it suitable for patient studies of CD1a in infectious disease. DDM analogs differing in the stereochemistry of their butyrate or oxazoline moieties were not recognized by human T cells. Therefore, we conclude that T cells show precise specificity for both arms of the peptide, which are predicted to lie at the CD1a-T cell receptor interface.

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Peptide synthesis by a combination of solid-phase and solution methods I: A new very acid-labile anchor group for the solid phase synthesis of fully protected fragments

Cited by 175 publications

References 14 publications

Enlarged Scale Chemical Synthesis and Range of Activity of Drosocin, an O‐Glycosylated Antibacterial Peptide of Drosophila

Enlarged Scale Chemical Synthesis and Range of Activity of Drosocin, an O‐Glycosylated Antibacterial Peptide of Drosophila

Precision Substrate Targeting of Protein Kinases v-Abl and c-Src

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

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