1.
Roles of tRNA in cell wall biosynthesis.
Source
Department of Microbiology, Ohio State University, Columbus, OH, USA.
Abstract
Recent research into various aspects of bacterial metabolism such as cell wall and antibiotic synthesis, degradation pathways, cellular stress, and amino acid biosynthesis has elucidated roles of aminoacyl-transfer ribonucleic acid (aa-tRNA) outside of translation. Although the two enzyme families responsible for cell wall modifications, aminoacyl-phosphatidylglycerol synthases (aaPGSs) and Fem, were discovered some time ago, they have recently become of intense interest for their roles in the antimicrobial resistance of pathogenic microorganisms. The addition of positively charged amino acids to phosphatidylglycerol (PG) by aaPGSs neutralizes the lipid bilayer making the bacteria less susceptible to positively charged antimicrobial agents. Fem transferases utilize aa-tRNA to form peptide bridges that link strands of peptidoglycan. These bridges vary among the bacterial species in which they are present and play a role in resistance to antibiotics that target the cell wall. Additionally, the formation of truncated peptides results in shorter peptide bridges and loss of branched linkages which makes bacteria more susceptible to antimicrobials. A greater understanding of the structure and substrate specificity of this diverse enzymatic family is necessary to aid current efforts in designing potential bactericidal agents. These two enzyme families are linked only by the substrate with which they modify the cell wall, aa-tRNA; their structure, cell wall modification processes and the physiological changes they impart on the bacterium differ greatly. WIREs RNA 2012. doi: 10.1002/wrna.1108 For further resources related to this article, please visit the WIREs website.
Copyright © 2012 John Wiley & Sons, Ltd.
- PMID:
- 22262511
- [PubMed - as supplied by publisher]
Mapping of B cell epitopes on desmoglein 3 in pemphigus vulgaris patients by the use of overlapping peptides.
Source
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Abstract
BACKGROUND:
Pemphigus vulgaris (PV) is a severe autoimmune blistering disease associated with autoantibodies to desmoglein 3 (Dsg 3), a transmembrane glycoprotein of the cadherin family. Previous studies mainly focused on the mapping of conformational epitopes of Dsg 3 using recombinant fragments of Dsg 3 and competition ELISA.
OBJECTIVE:
Here, we performed a mapping of linear B cell epitopes on Dsg 3 in PV patients by the use of overlapping synthetic peptides.
METHODS:
A set of 254 overlapping synthetic peptides of 14 amino acids length covering the entire Dsg 3 extracellular domain was generated. Sera of patients with active PV (n=10) and healthy volunteers (n=10) were tested for IgG reactivity with the 254 peptides by ELISA. Testing each peptide separately, 7 major antigenic sites were identified. In order to validate these reactivities, 7 corresponding peptides of 13-33 amino acids in length were generated and employed by ELISA. Additional sera of active PV patients (n=17) and healthy volunteers (n=20) were tested and the most reactive peptide was used to specifically purify anti-Dsg 3 antibodies from PV sera (n=3).
RESULTS:
The major autoantibody reactivity in PV sera was mapped to amino acids 333-356 within the EC3 domain. Purifying patients IgG using the identified peptide, however, failed to induce acantholysis in keratinocyte dissociation assay.
CONCLUSION:
We conclude that linear epitopes do not play a major pathogenic role in human PV.
Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
- PMID:
- 22261006
- [PubMed - as supplied by publisher]
Comprehensive Conformational Studies of Five Tripeptides and a Deduced Method for Efficient Determinations of Peptide Structures.
Abstract
Thorough searches on the potential energy surfaces of five tripeptides, GGG, GYG, GWG, TGG and MGG, were performed by considering all possible combinations of the bond rotational degrees of freedom with a semi-empirical and ab initio combined computational approach. Structural characteristics of the obtained stable tripeptide conformers were carefully analyzed. Conformers of the five tripeptides were found to be closely connected with conformers of their constituting dipeptides and amino acids. A method for finding all important tripeptide conformers by optimizing a small number of trial structures generated by suitable superposition of the parent amino acid and dipeptide conformers is thus proposed. Applying the method to another five tripeptides, YGG, FGG, WGG, GFA and GGF, studied before shows that the new approach is both efficient and reliable by providing the most complete ensembles of tripeptide conformers. The method is further generalized for application to larger peptides by introducing the breeding and mutation concepts in a genetic algorithm way. The generalized method is verified to be capable of finding tetrapeptide conformers with secondary structures of strands, helices and turns which are highly populated in larger peptides. This show some promise for the proposed method to be applied for the structural determination of larger peptides.
- PMID:
- 22260814
- [PubMed - as supplied by publisher]
Binding of a truncated form of Lecithin : retinol acyltransferase and its N- and C-terminal peptides to lipid monolayers.
Abstract
Lecithin retinol acyltransferase (LRAT) is a 230 amino acids membrane-associated protein which catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester. A truncated form of LRAT (tLRAT), which contains the residues required for catalysis but which is lacking the N- and C-terminal hydrophobic segments, was produced to study its membrane binding properties. Measurements of the maximum insertion pressure of tLRAT, which is higher than the estimated lateral pressure of membranes, and the positive synergy factor a argue in favor of a strong binding of tLRAT to phospholipid monolayers. Moreover, the binding, secondary structure and orientation of the peptides corresponding to the N- and C-terminal hydrophobic segments of LRAT have been studied by circular dichroism and polarization-modulation infrared reflection absorption spectroscopy in monolayers. The results show that these peptidesspontaneously bind to lipid monolayers and adopt an alpha helical secondary structure. On the basis of these data, a new membrane topology model of LRAT is proposed where its N- and C-terminal segments allow to anchor this protein to the lipid bilayer.
- PMID:
- 22260449
- [PubMed - as supplied by publisher]
Comparative analysis of recombinant Human Papillomavirus 8 L1 production in plants by a variety of expression systems and purification methods.
Source
Istituto di Virologia Vegetale, CNR, Strada delle Cacce, Torino, Italy.
Abstract
Human papillomavirus 8 (HPV-8), one of the high-risk cutaneous papillomaviruses (cHPVs), is associated with epidermodysplasia verruciformis and nonmelanoma skin cancer in immuno-compromised individuals. Currently, no vaccines against cHPVs have been reported; however, recent studies on cross-neutralizing properties of their capsid proteins (CP) have fostered an interest in vaccine production against these viruses. We examined the potential of producing HPV-8 major CP L1 in Nicotiana benthamiana by agroinfiltration of different transient expression vectors: (i) the binary vector pBIN19 with or without silencing suppressor constructs, (ii) the nonreplicating Cowpea mosaic virus-derived expression vector pEAQ-HT and (iii) a replicating Tobacco mosaic virus (TMV)-based vector alone or with signalpeptides. Although HPV-8 L1 was successfully expressed using pEAQ-HT and TMV, a 15-fold increase was obtained with pEAQ-HT. In contrast, no L1 protein could be immune detected using pBIN19 irrespective of whether silencing suppressors were coexpressed, although such constructs were required for identifying L1-specific transcripts. A fourfold yield increase in L1 expression was obtained when 22 C-terminal amino acids were deleted (L1ΔC22), possibly eliminating a nuclear localization signal. Electron microscopy showed that plant-made HPV-8 L1 proteins assembled in appropriate virus-like particles (VLPs) of T = 1 or T = 7 symmetry. Ultrathin sections of L1ΔC22-expressing cells revealed their accumulation in the cytoplasm in the form of VLPs or paracrystalline arrays. These results show for the first time the production and localization of HPV-8 L1 protein in planta and its assembly into VLPs representing promising candidate for potential vaccine production.
© 2012 The Authors. Plant Biotechnology Journal © 2012 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.
- PMID:
- 22260326
- [PubMed - as supplied by publisher]
A novel family of peptides with potent activity against influenza A viruses.
Source
University of Edinburgh.
Abstract
The emergence of drug resistant strains of influenza virus has catalyzed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the HIV entry blocker Enfuvirtide, there has been a resurgence of interest in peptide based antivirals. In this paper we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque reduction assay we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 amino acidsthat binds to HA and inhibits infection. Using a mouse model of intranasal influenza virus infection we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic.
Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract.
Source
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 3E2, Canada; Email: alireza.jahanmihan@utoronto.ca (A.J.-M.); bohdan.luhovyy@utoronto.ca (B.L.L.); dalia.elkhoury@utoronto.ca (D.E.K.).
Abstract
Dietary proteins elicit a wide range of nutritional and biological functions. Beyond their nutritional role as the source ofamino acids for protein synthesis, they are instrumental in the regulation of food intake, glucose and lipid metabolism, blood pressure, bone metabolism and immune function. The interaction of dietary proteins and their products of digestion with the regulatory functions of the gastrointestinal (GI) tract plays a dominant role in determining the physiological properties of proteins. The site of interaction is widespread, from the oral cavity to the colon. The characteristics of proteins that influence their interaction with the GI tract in a source-dependent manner include their physico-chemical properties, their amino acid composition and sequence, their bioactive peptides, their digestion kinetics and also the non-protein bioactive components conjugated with them. Within the GI tract, these products affect several regulatory functions by interacting with receptors releasing hormones, affecting stomach emptying and GI transport and absorption, transmitting neural signals to the brain, and modifying the microflora. This review discusses the interaction of dietary proteins during digestion and absorption with the physiological and metabolic functions of the GI tract, and illustrates the importance of this interaction in the regulation of amino acid, glucose, lipid metabolism, and food intake.
Novel Nonphosphorylated Peptides with Conserved Sequences Selectively Bind to Grb7 SH2 Domain with Affinity Comparable to Its Phosphorylated Ligand.
Source
National Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China.
Abstract
The Grb7 (growth factor receptor-bound 7) protein, a member of the Grb7 protein family, is found to be highly expressed in such metastatic tumors as breast cancer, esophageal cancer, liver cancer, etc. The src-homology 2 (SH2) domain in the C-terminus is reported to be mainly involved in Grb7 signaling pathways. Using the random peptide library, we identified a series of Grb7 SH2 domain-binding nonphosphorylated peptides in the yeast two-hybrid system. Thesepeptides have a conserved GIPT/K/N sequence at the N-terminus and G/WD/IP at the C-terminus, and the region between the N-and C-terminus contains fifteen amino acids enriched with serines, threonines and prolines. The association between the nonphosphorylated peptides and the Grb7 SH2 domain occurred in vitro and ex vivo. When competing for binding to the Grb7 SH2 domain in a complex, one synthesized nonphosphorylated ligand, containing the twenty-two amino acid-motif sequence, showed at least comparable affinity to the phosphorylated ligand of ErbB3 in vitro, and its overexpression inhibited the proliferation of SK-BR-3 cells. Such nonphosphorylated peptides may be useful for rational design of drugs targeted against cancers that express high levels of Grb7 protein.
A novel molluscan sigma-like glutathione S-transferase from Manila clam, Ruditapes philippinarum: Cloning, characterization and transcriptional profiling.
Source
Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju Special Self-Governing Province, 690-756, Republic of Korea.
Abstract
Glutathione S-transferases (GSTs) are versatile enzymes, act as primary intracellular detoxifiers and contribute to a broad range of physiological processes including cellular defense. In this study, a full-length cDNA representing a novel sigma-like GST was identified from Manila clam, Ruditapes philippinarum (RpGSTσ). RpGSTσ (884bp) was found to possess an open reading frame of 609bp. The encoded polypeptide (203 amino acids) had a predicted molecular mass of 23.21kDa and an isoelectric point of 7.64. Sequence analysis revealed two conserved GST domain profiles in N- and C-termini. Alignment studies revealed that the identity between deduced peptides of RpGSTσ and known GSTσ members was relatively low (<35%), except a previously identified Manila clam GSTσ isoform (87.2%). Phylogenetic analysis indicated that RpGSTσ clustered together with molluscan GSTσ homologs, which were closely related to insect GSTσs. The RpGSTσ was subsequently cloned and expressed as recombinant protein, in order to characterize its biological activity. The recombinant RpGSTσ exhibited characteristic glutathione conjugating catalytic activity toward 1-chloro-2,4-dinitrobenzene, 3,4-dichloronitrobenzene and ethacrynic acid. It had an optimal pH and temperature of 8.0 and 35°C, respectively. Expression profiles under normal conditions and in response to lipopolysaccharide-, poly I:C- and Vibrio tapetis-challenges were also investigated. RpGSTσ demonstrated a differential tissue distribution with robust transcription in gills of normal animals. We explored potential association of GSTσ in cellular defense during bacterial infection and found that in challenged clams, RpGSTσ gene was significantly induced in internal and external tissues, in conjunction with manganese- as well as copper-zinc superoxide dismutase (MnSOD and CuZnSOD) genes. Moreover, the induction was remarkably higher in hemocytes than in gill. Collectively, our findings suggested that RpGSTσ could play a significant role in cellular defense against oxidative stress caused by bacteria, in conjunction with other antioxidant enzymes, such as SODs.
Copyright © 2012. Published by Elsevier Inc.
- PMID:
- 22245757
- [PubMed - as supplied by publisher]
Cell-penetrating properties of the transactivator of transcription and polyarginine (R9) peptides, their conjugative effect on nanoparticles and the prospect of conjugation with arsenic trioxide.
Source
aNanomedicine-Laboratory of Immunology and Molecular Biomedical Research (LIMBR), Centre for Biotechnology and Interdisciplinary Biosciences (BioDeakin), Institute for Technology and Research Innovation (ITRI), Geelong Technology Precinct (GTP), Deakin University, Geelong, Vic., Australia bNano-biotech Lab, Department of Zoology, K.M. College, University of Delhi, Delhi, India.
Abstract
Cell-penetrating peptides (CPPs) are short chains of amino acids with the distinct ability to cross cell plasma membranes. They are usually between seven and 30 residues in length. The mechanism of action is still a highly debated subject among researchers; it seems that a commonality between all CPPs is the presence of positively charged residues within the amino acid chain. Polyarginine and the transactivator of transcription peptide are two widely used CPPs. One distinct application of these CPPs is the ability to further enhance the therapeutic properties of a range of different agents. One group of agents of particular importance are nanoparticles (NPs). Most NPs have no mechanism for cellular uptake. Hence, by conjugating CPPs to NPs, the amount of NPs taken up by cells can be increased, and therefore, the therapeutic benefits can be maximized. Some examples of this will be explored further in this review. In addition to CPPs, the concept of conjugation with the anticancer drug arsenic trioxide is reviewed and the prospect of transactivator of transcription-conjugated arsenic trioxide albumin microspheres is also discussed. Recent locked nucleic acid technology to stabilize nucleotides (RNA or DNA) aptamer complexes able to target cancer cells more specifically and selectively to kill tumour cells and spare normal body cells. NPs tagged with modified locked nucleic acid-aptamers have the potential to kill cancer cells more specifically and effectively while sparing normal cells.
Structural and Energetic Effects in the Molecular Recognition of Protonated Peptidomimetic Bases by 18-Crown-6.
Abstract
Absolute 18-crown-6 (18C6) affinities of nine protonated peptidomimetic bases are determined using guided ion beam tandem mass spectrometry techniques. The bases (B) included in this work are mimics for the n-terminal amino group and the side chains of the basic amino acids, i.e., the favorable sites for binding of 18C6 to peptides and proteins. Isopropylamine is chosen as a mimic for the n-terminal amino group, imidazole and 4-methylimidazole are chosen as mimics for the side chain of histidine (His), 1-methylguanidine is chosen as a mimic of the side chain of arginine (Arg), and several primary amines including: methylamine, ethylamine, n-propylamine, n-butylamine, and 1,5-diamino pentane as mimics for the side chain of lysine (Lys). Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the peptidomimetic bases, as well as the proton bound complexes comprised of these species, (B)H+(18C6). The measured 18C6 binding affinities of the Lys side chain mimics are larger than the measured binding affinities of the mimics for Arg and His. These results suggest that the Lys side chains should be the preferred binding sites for 18C6 complexation to peptides and proteins. Present results also suggest that competition between Arg or His and Lys for 18C6 is not significant. The mimic for the n-terminal aminogroup, exhibits a measured binding affinity for 18C6 that is similar to or greater than that of the Lys side chain mimics. However, theory suggests that binding to n-terminal amino group mimic is weaker than to all of the Lys mimics. These results suggest that the n-terminal amino group may compete with the Lys side chains for 18C6 complexation.
Identification of Interaction Site of Propeptide toward Mature Carboxypeptidase Y (mCPY) Based on the Similarity between Propeptide and CPY Inhibitor (I(C)).
Source
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University.
Abstract
Both the propeptide in the precursor carboxypeptidase Y (proCPY) and the mature CPY (mCPY)-specific endogenous inhibitor (I(C)) inhibit CPY activity. The N-terminal inhibitory reactive site of I(C) (the N-terminal seven amino acids of I(C)) binds to the substrate-binding site of mCPY and is essential for mCPY inhibition, but the mechanism of mCPY inhibition by the propeptide is poorly understood. In this study, sequence alignment between I(C) and proCPY indicated that a sequence similar to the N-terminal region of I(C) was present in proCPY. In particular, a region including the C-terminus of the propeptide was similar to the N-terminal seven amino acids of I(C). In the presence of peptides identical to the N-terminus of I(C) and the C-terminus of the propeptide, CPY activity was competitively inhibited. The C-terminal region of the propeptide might bind to the substrate-binding site of mCPY.
Cis-trans peptide variations in structurally similar proteins.
Source
INSERM UMR-S 665, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Université Denis Diderot-Paris 7, INTS, 6, rue Alexandre Cabanel, 75739, Paris Cedex 15, France.
Abstract
The presence of energetically less favourable cis peptides in protein structures has been observed to be strongly associated with its structural integrity and function. Inter-conversion between the cis and trans conformations also has an important role in the folding process. In this study, we analyse the extent of conservation of cis peptides among similar folds. We look at both the amino acid preferences and local structural changes associated with such variations. Nearly 34% of the Xaa-Proline cis bonds are not conserved in structural relatives; Proline also has a high tendency to get replaced by another amino acid in the trans conformer. At both positions bounding the peptide bond, Glycine has a higher tendency to lose the cis conformation. The cis conformation of more than 30% of β turns of type VIb and IV are not found to be conserved in similar structures. A different view using Protein Block-based description of backbone conformation, suggests that many of the local conformational changes are highly different from the general local structural variations observed among structurally similar proteins. Changes between cis and trans conformations are found to be associated with the evolution of new functions facilitated by local structural changes. This is most frequent in enzymes where new catalytic activity emerges with local changes in the active site. Cis-trans changes are also seen to facilitate inter-domain and inter-protein interactions. As in the case of folding, cis-trans conversions have been used as an important driving factor in evolution.
Structure and function of OprD protein in Pseudomonas aeruginosa: From antibiotic resistance to novel therapies.
Source
Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Abstract
Pseudomonas aeruginosa (P. aeruginosa) is a common pathogen isolated from patients with nosocomial infections. Due to its intrinsic and acquired antimicrobial resistance, limited classes of antibiotics can be used for the treatment of infection with P. aeruginosa. Of these, the carbapenems are very important; however, the occurrence of carbapenem-resistant strains is gradually increasing over time. Deficiency of the outer membrane protein OprD confers P. aeruginosa a basal level of resistance to carbapenems, especially to imipenem. Functional studies have revealed that loops 2 and 3 in the OprD protein contain the entrance and/or binding sites for imipenem. Therefore, any mutation in loop 2 and/or loop 3 that causes conformational changes could result in carbapenem resistance. OprD is also a common channel for someamino acids and peptides, and competition with carbapenems through the channel may also occur. Furthermore, OprD is a highly regulated protein at transcriptional and post-transcriptional levels by some metals, small bioactive molecules,amino acids, and efflux pump regulators. Because of its hypermutability and highly regulated properties, OprD is thought to be the most prevalent mechanism for carbapenem resistance in P. aeruginosa. Developing new strategies to combat infection with carbapenem-resistant P. aeruginosa lacking OprD is an ongoing challenge.
Copyright © 2011 Elsevier GmbH. All rights reserved.
Fine-tuning the π-π Aromatic Interactions in Peptides: Somatostatin Analogues Containing Mesityl Alanine.
Source
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac, 10, 08028 Barcelona (Spain).
Abstract
The π-π aromatic interactions between amino acids 6, 7, and 11 in the natural hormone somatostatin are crucial for conformational stability. In their Communication (DOI: 10.1002/anie.201106406), M. J. Macias, A. Riera, and co-workers describe that peptidic analogues obtained by replacing each phenylalanine with mesitylalanine are conformationally more rigid than the parent hormone. This strategy has yielded the first 3D structures of 14-amino-acid somatostatin analogues.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
A comprehensive library of blocked dipeptides reveals intrinsic backbone conformational propensities of unfolded proteins.
Source
Department of Chemistry, Korea University, Seoul 136-701, Korea.
Abstract
Despite prolonged scientific efforts to elucidate the intrinsic peptide backbone preferences of amino-acids based on understanding of intermolecular forces, many open questions remain, particularly concerning neighboring peptide interaction effects on the backbone conformational distribution of short peptides and unfolded proteins. Here, we show that spectroscopic studies of a complete library of 400 dipeptides reveal that, irrespective of side-chain properties, the backbone conformation distribution is narrow and they adopt polyproline II and β-strand, indicating the importance of backbone peptide solvation and electronic effects. By directly comparing the dipeptide circular dichroism and NMR results with those of unfolded proteins, the comprehensive dipeptides form a complete set of structural motifs of unfolded proteins. We thus anticipate that the present dipeptide library with spectroscopic data can serve as a useful database for understanding the nature of unfolded protein structures and for further refinements of molecular mechanical parameters. Proteins 2011; © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
The role of a conserved threonine residue in the leader peptide of lasso peptide precursors.
Source
Department of Chemical and Biological Engineering, A207 Engineering Quadrangle, Princeton University, Princeton, NJ 08544, USA. ajlink@princeton.edu.
Abstract
The conserved threonine (Thr) residue in the penultimate position of the leader peptide of lasso peptides microcin J25 and capistruin can be effectively replaced by several amino acids close in size and shape to Thr. These findings suggest a model for lasso peptide biosynthesis in which the Thr sidechain is a recognition element for the lasso peptide maturation machinery.
Fluorinated and iodinated (Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
Fluorinated and iodinated (Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 3), abbreviated as [18F]3 and [125I]3, respectively, is an aurone derivative synthesized by Watanabe et al. for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) plaques (1). AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (6, 7). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (1, 8, 9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT) (7). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (6, 7). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a-c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [125I]3 and [18F]3 (1).
Sections
Radioiodinated (Z)-2-(4-(2-hydroxyethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
Radioiodinated (Z)-2-(4-(2-hydroxyethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 15), abbreviated as [125I]15, is an aurone derivative synthesized by Maya et al. for single-photon emission computed tomography(SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1). The other four aurone derivatives include radioiodinated (Z)-2-(4-methoxybenzylidene)-5-iodobenzofuran-3(2H)-one (compound 9), (Z)-2-(4-hydroxybenzylidene)-5-iodobenzofuran-3(2H)-one (compound 14), (Z)-2-(4-(2-(2-hydroxyethoxy)ethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 16), and (Z)-2-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 17), which are abbreviated as [125I]9, [125I]14, [125I]16, and [125I]17, respectively. AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (6, 7). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (1, 8, 9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT) (7). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (6, 7). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [125I]15, [125I]9, [125I]14, [125I]16, and [125I]17 (1).
Sections
99mTc-Bis-amino-bis-thiol-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
99mTc-Bis-amino-bis-thiol (BAT)-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one, abbreviated as [99mTc]BAT-FL and [99mTc]BAT-AR, respectively, are flavone and aurone derivatives synthesized by Ono et al. for single-photon emission computed tomography (SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1). AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (1, 6). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (7-9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (1, 6). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [99mTc]BAT-FL and [99mTc]BAT-AR (1).
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