-
Journal of Peptide Science : An... Jan 2016Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale... (Review)
Review
Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.
Topics: Amino Acids; Aspartic Acid; Cell Line; Epithelial Cells; Fluorenes; Glycosylation; Humans; Methylation; Peptides; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Solid-Phase Synthesis Techniques
PubMed: 26785684
DOI: 10.1002/psc.2836 -
Aging Nov 2022
Topics: Isoaspartic Acid; Amino Acid Sequence; Aspartic Acid
PubMed: 36446387
DOI: 10.18632/aging.204420 -
Magnetic Resonance in Medicine Oct 2017To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to...
PURPOSE
To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics.
METHODS
Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation.
RESULTS
The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho.
CONCLUSION
The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med 78:1235-1245, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Topics: Adult; Aspartic Acid; Brain; Choline; Creatine; Diffusion; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Spectroscopy; Phantoms, Imaging
PubMed: 27797114
DOI: 10.1002/mrm.26514 -
Acta Biomaterialia Feb 2017Poly(aspartic acid) (PASP) derivatives with adjustable pH-dependent solubility were synthesized and characterized to establish the relationship between their structure...
UNLABELLED
Poly(aspartic acid) (PASP) derivatives with adjustable pH-dependent solubility were synthesized and characterized to establish the relationship between their structure and solubility in order to predict their applicability as a basic material for enteric coatings. Polysuccinimide, the precursor of PASP, was modified with short chain alkylamines, and the residual succinimide rings were subsequently opened to prepare the corresponding PASP derivatives. Study of the effect of the type and concentration of the side groups on the pH-dependent solubility of PASP showed that solubility can be adjusted by proper selection of the chemical structure. The Henderson-Hasselbalch (HH) and the extended HH equations were used to describe the pH-dependent solubility of the polymers quantitatively. The estimate provided by the HH equation is poor, but an accurate description of the pH-dependent solubility can be found with the extended HH equation. The dissolution rate of a polymer film prepared from a selected PASP derivative was determined by fluorescence marking. The film dissolved rapidly when the pH was increased above its pK. Cellular viability tests show that PASP derivatives are non-toxic to a human cell line. These polymers are thus of great interest as starting materials for enteric coatings.
STATEMENT OF SIGNIFICANCE
Poly(amino acid) type biocompatible polymers were synthesized for future use as pharmaceutical film coatings. To this end, we tailored the pH-dependent solubility of poly(aspartic acid) (PASP). It was found that both the solubility and the pK values of the modified PASP depended strongly on composition. Fluorescent marking was used to characterize the dissolution of a chosen PASP derivative. In acidic media only a negligible amount of the polymer dissolved, but dissolution was very fast and complete at the pH values that prevail in the small intestine. As a consequence, enteric coatings based on such PASP derivatives may be used for drug delivery in the gastrointestinal tract.
Topics: Aspartic Acid; Cell Line, Tumor; Cell Survival; Humans; Hydrogen-Ion Concentration; Models, Theoretical; Peptides; Proton Magnetic Resonance Spectroscopy; Solubility
PubMed: 27915021
DOI: 10.1016/j.actbio.2016.11.065 -
Biological & Pharmaceutical Bulletin Sep 2005D-Aspartate (D-Asp) is an endogenous amino acid present in nervous and endocrine tissues in mammals. A high concentration of D-Asp is observed in embryos, which... (Review)
Review
D-Aspartate (D-Asp) is an endogenous amino acid present in nervous and endocrine tissues in mammals. A high concentration of D-Asp is observed in embryos, which disappears in nervous tissues after delivery, but increases temporarily in endocrine glands, particularly in the pituitary, pineal and adrenal glands at the specific stages. In the pineal gland, D-Asp that is apparently derived from other tissues suppresses melatonin secretion from parenchymal cells. Additionally, D-Asp levels increase in the testis just before birth and during maturation. The amino acid is presumed to be synthesized by the pituitary gland and testis. In the testis, D-Asp produced inside the seminiferous tubules acts on Leydig cells following release to enhance testosterone synthesis by activating the expression of Steroidogenic Acute Regulatory protein. Mammalian cells appear to contain all the molecular components required to regulate D-Asp homeostasis, as they can synthesize, release, take up, and degrade the amino acid. These findings collectively indicate that D-Asp is a novel type of messenger in the mammalian body.
Topics: Animals; Aspartic Acid; Humans; Mammals
PubMed: 16141517
DOI: 10.1248/bpb.28.1566 -
Journal of the American Chemical Society Nov 2019The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high...
The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine -oxides further document the utility of this approach. Demonstration of the asymmetric -oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
Topics: Aspartic Acid; Catalysis; Heterocyclic Compounds; Hydrogen Bonding; Peptides; Pyridines; Stereoisomerism
PubMed: 31656070
DOI: 10.1021/jacs.9b10414 -
Journal of Virology Apr 2022The reovirus attachment protein σ1 mediates cell attachment and receptor binding and is thought to undergo conformational changes during viral disassembly. σ1 is a...
The reovirus attachment protein σ1 mediates cell attachment and receptor binding and is thought to undergo conformational changes during viral disassembly. σ1 is a trimeric filamentous protein with an α-helical coiled-coil tail, a triple-β-spiral body, and a globular head. At the trimer interface, the head domain features an unusual and conserved aspartic acid cluster, which forms the only significant intratrimer interactions in the head and must be protonated to allow trimer formation. To define the role of pH on σ1 stability and conformation, we tested its domains over a wide range of pH values. We show that all domains of σ1 are remarkably thermostable, even at the low pH of the stomach. We determined the optimal pH for stability to be between pHs 5 and 6, a value close to the pH of the endosome and of the jejunum. The σ1 head is stable at acidic and neutral pH but detrimerizes at basic pH. When Asp in the aspartic acid cluster is mutated to asparagine (D345N), the σ1 head loses stability at low pH and is more prone to detrimerize. Although the D345N mutation does not affect σ1 binding affinity for the JAM-A receptor, the overall binding stoichiometry is reduced by one-third. The additional replacement of the neighboring His with alanine disrupts inner trimer surface interactions, leading to a less thermostable and monomeric σ1 D345N head that fails to bind the JAM-A receptor. When the body is expressed together with the head domain, the thermostability is restored and the stoichiometry of the binding to JAM-A receptor is preserved. Our results confirm a fundamental role of the aspartic acid cluster as a pH-dependent molecular switch controlling trimerization and enhancing thermostability of σ1, which represent essential requirements to accomplish reovirus infection and entry and might be common mechanisms among other enteric viruses. Enteric viruses withstand the highly acidic environment of the stomach during transmission, and many of them use low pH as a trigger for conformational changes associated with entry. For many nonenveloped viruses, the structural basis of these effects is not clear. We have investigated the stability of the reovirus attachment protein σ1 over a range of pHs and find it to be remarkably thermostable, especially at low pH. We identify a role for the aspartic acid cluster in maintaining σ1 thermostability, trimeric organization, and binding to JAM-A receptor especially at the gastric pH reovirus has to withstand while passing the stomach. The understanding of monomer-trimer dynamics within σ1 enhances our knowledge of reovirus entry and has implications for stability and transmission of other enteric viruses.
Topics: Aspartic Acid; Humans; Hydrogen-Ion Concentration; Polymers; Protein Stability; Reoviridae; Reoviridae Infections; Viral Nonstructural Proteins
PubMed: 35380459
DOI: 10.1128/jvi.00331-22 -
Magnetic Resonance in Medical Sciences... 2015Proton magnetic resonance spectroscopy (MRS) allows the noninvasive exploration of tissue metabolism in vivo, providing neurophysiological and neurochemical information.... (Review)
Review
Proton magnetic resonance spectroscopy (MRS) allows the noninvasive exploration of tissue metabolism in vivo, providing neurophysiological and neurochemical information. N-acetylaspartate (NAA) is generally considered to be a marker of neurons and axons, and many neurodegenerative disorders, including demyelinating disorders, exhibit a decrease in total NAA (tNAA). MRS in human hypomyelination disorders, such as Pelizaeus-Merzbacher disease (PMD), is characterized by normal to elevated tNAA, elevated myo-inositol and creatine (Cr), and normal to decreased choline (Cho). MRS in the thalamus of a hypomyelinating mouse model, a myelin synthesis-deficient (msd) mouse, a model of connatal PMD with mutation of the Plp1 gene, revealed increased tNAA and Cr and decreased Cho. That of a shiverer mouse with an autosomal recessive mutation of the Mbp gene showed decreased Cho with normal tNAA and Cr. Accordingly, the reduction of Cho on MRS might be a common marker for hypomyelinating disorders. tNAA concentrations range from normal to increased, probably depending upon the underlying pathology of oligodendrocytes. tNAA may be increased in hypomyelination with a reduced number of mature oligodendrocytes, such as PMD.
Topics: Animals; Aspartic Acid; Brain Chemistry; Choline; Creatine; Demyelinating Diseases; Disease Models, Animal; Humans; Mice; Pelizaeus-Merzbacher Disease; Proton Magnetic Resonance Spectroscopy
PubMed: 26185828
DOI: 10.2463/mrms.2014-0064 -
Carbohydrate Research Aug 2016We describe the synthesis and characterization of 6-phosphofructose-aspartic acid, an intermediate in the metabolism of fructose-asparagine by Salmonella. We also report...
We describe the synthesis and characterization of 6-phosphofructose-aspartic acid, an intermediate in the metabolism of fructose-asparagine by Salmonella. We also report improved syntheses of fructose-asparagine itself and of fructose-aspartic acid.
Topics: Asparagine; Aspartic Acid; Fructosephosphates; Molecular Structure
PubMed: 27258673
DOI: 10.1016/j.carres.2016.05.003 -
Cold Spring Harbor Symposia on... 2011Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes,... (Review)
Review
Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes, metabolomics can point to potential new sites for therapeutic intervention. Particularly promising enzymatic targets are those that carry increased flux in the disease state. Definitive assessment of flux requires the use of isotope tracers. Here we present techniques for finding new drug targets using metabolomics and isotope tracers. The utility of these methods is exemplified in the study of three different viral pathogens. For influenza A and herpes simplex virus, metabolomic analysis of infected versus mock-infected cells revealed dramatic concentration changes around the current antiviral target enzymes. Similar analysis of human-cytomegalovirus-infected cells, however, found the greatest changes in a region of metabolism unrelated to the current antiviral target. Instead, it pointed to the tricarboxylic acid (TCA) cycle and its efflux to feed fatty acid biosynthesis as a potential preferred target. Isotope tracer studies revealed that cytomegalovirus greatly increases flux through the key fatty acid metabolic enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme blocks human cytomegalovirus replication. Examples where metabolomics has contributed to identification of anticancer drug targets are also discussed. Eventual proof of the value of metabolomics as a drug target discovery strategy will be successful clinical development of therapeutics hitting these new targets.
Topics: Antineoplastic Agents; Antiviral Agents; Aspartic Acid; Drug Discovery; Humans; Isotope Labeling; Metabolomics
PubMed: 22114327
DOI: 10.1101/sqb.2011.76.010694