Biomedical subjects

Xiaobing Wang

Publications and source records attributed to Xiaobing Wang.

12 recordsLinked to original sources

PubMed2006

Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "staged" inhibitor design.

4-Amino-4-deoxychorismate synthase (ADCS) catalyzes the first step in the conversion of chorismate into p-aminobenzoate, which is incorporated into folic acid. We aim to discover compounds that inhibit ADCS and serve as leads for a new class of antimicrobial compounds. This report presents (1) synthesis of a mass-tag encoded library based on a "staged" design, (2) massively parallel fluorescence-based on-bead screening, (3) rapid structural identification of hits, and (4) full kinetic analysis of ADCS. All inhibitors are competitive against chorismate and Mg(2+). The most potent ADCS inhibitor identified has a K(i) of 360 microM. We show that the combinatorial diversity elements add substantial binding affinity by interacting with residues outside of but proximal to the active site. The methods presented here constitute a paradigm for inhibitor discovery through active site targeting, enabled by rapid library synthesis, facile massively parallel screening, and straightforward hit identification.

Acetates↗

PubMed2006

Sonodynamic effects of protoporphyrin IX disodium salt on isolated sarcoma 180 cells.

The cytotoxic effect of PPIX on isolated sarcoma 180 cells induced by ultrasound was investigated. Tumor cells suspended in air-saturated PBS (pH 7.2) were exposed to ultrasound at 2.2 MHz for up to 60s in the presence and absence of protoporphyrin IX disodium salt (PPIX). The viability of cells was determined by a trypan blue exclusion test. The rate of ultrasonically induced cell damage was increased with 40-160 microM PPIX, while no cell damage was observed with 160 microM PPIX alone. This enhancement of cell damage with PPIX was inhibited by histidine. The participation of lipid peroxidation products in the cell damage process was also investigated. Scanning electron microscope (SEM) observation of the surface of cells was performed to evaluate the morphological changes induced by ultrasonic irradiation. The results indicate the involvement of a sonochemical mechanism.

Animals↗

PubMed2006

A general approach to porous crystalline TiO2, SrTiO3, and BaTiO3 spheres.

Monodispersed porous crystalline TiO(2), SrTiO(3), and BaTiO(3) spheres were produced through a one-step hydrothermal process from amorphous TiO(2) spheres. The resulting samples were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and nitrogen sorption measurements. On the basis of the characterization results, we proposed a formation process of these porous spheres according to a mechanism analogous to the Kirkendall effect. This study provides a general way to synthesize porous titania-based spheres.

Adsorption↗

PubMed2006

Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging.

Small peptide-based agents have attracted wide interest as cancer-targeting agents for diagnostic imaging and targeted therapy. There is a need to develop new high-affinity and high-specificity peptidomimetic or small-molecule ligands against cancer cell surface receptors. Here we report on the identification of a high-affinity peptidomimetic ligand (LLP2A; IC50 = 2 pM) against alpha4beta1 integrin using both diverse and highly focused one-bead-one-compound combinatorial peptidomimetic libraries in conjunction with high-stringency screening. We further demonstrate that LLP2A can be used to image alpha4beta1-expressing lymphomas with high sensitivity and specificity when conjugated to a near infrared fluorescent dye in a mouse xenograft model. Thus, LLP2A provides an important tool for noninvasive monitoring of alpha4beta1 expression and activity during tumor progression, and it shows great potential as an imaging and therapeutic agent for alpha4beta1-positive tumors.

Animals↗

PubMed2006

Advance in antitumor agents targeting glutathione-S-transferase.

Glutathione-S-transferases (GSTs; EC 2.5.1.18), a family of phase II detoxification enzymes, catalyze the conjugation of glutathione with broad substrates including chemotherapeutic agents, and are involved in cell protection against apoptotic signals by inhibiting the stress-signaling cascade mediated by ASK1 (Apoptosis signal-regulating kinase)-JNK (c-Jun N-terminal kinase). As GSTs are overexpressed in some malignant tumors, GSTs is a promising therapeutic target. This article reviews the progress in the development of GSTs inhibitors and GSTs activated prodrugs.

Animals↗

PubMed2005

Synthesis and structure-activity relationship of ethacrynic acid analogues on glutathione-s-transferase P1-1 activity inhibition.

Ethacrynic acid (EA) is a glutathione-s-transferase pi (GSTP1-1) inhibitor. Fifteen of EA analogues were designed and synthesized and their inhibition on GSTP1-1 activity was tested in lysate of human leukemia HL-60 cells. These compounds were synthesized using substituted phenol as precursors through reacting with 2-chlorocarboxylic acid and acylation. Structure-activity analysis indicates that replacements of chlorides of EA by methyl, bromide, and fluoride at 3' position remain the GSTP1-1 inhibitory effect. The compounds without any substitute at 3' position lose the activity on GSTP1-1 inhibition. These data suggest that the substitution of 3' position of EA is necessary for inhibiting GSTP1-1 activity.

Animals↗

PubMed2005

Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid.

Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

Amino Acid Sequence↗

PubMed2004

Encoding method for OBOC small molecule libraries using a biphasic approach for ladder-synthesis of coding tags.

In the "one-bead one-compound" (OBOC) combinatorial library method, each compound bead displays only one compound entity. Hundreds of thousands to millions of compound beads can be synthesized rapidly and screened simultaneously. Positive compound beads are then isolated for structural analysis. To fully exploit the power of OBOC combinatorial small molecule libraries, a robust and high throughput encoding method is needed to decode the positive compound beads. In this paper, we report on the development of a novel encoding strategy that combines the concepts of ladder-synthesis and chemical encoding on bilayer beads. In these encoded libraries, small molecule compounds are displayed on the bead surface, and cleavable coding tags consisting of a series of truncated molecules reside in the bead interior. Such a library can be easily constructed using the biphasic approach (J. Am. Chem. Soc.2002, 124, 7678) to topologically segregate the functionalities of the beads during library synthesis. The ladder members and coding tags are then released for MALDI-TOF-MS analysis. To simplify the interpretation of the mass spectra, we purposely add bromine into the cleavable linker so that the cleavage products generate a characteristic isotope fingerprint. The chemical structure of library compounds can be determined by analyzing the mass differences between adjacent peaks on the mass spectra. This encoding strategy also provides valuable information on the quality of the testing compound on the surface of the bead. To validate this methodology, a model OBOC small molecule library with 12,288 members was synthesized on TentaGel beads and screened against streptavidin. The chemical structures of the compound on each positive bead were unambiguously identified.

Amino Acids↗

PubMed2004

Synthesis of hydrophilic and flexible linkers for peptide derivatization in solid phase.

Four N-Fmoc protected polyoxyethylene-based amino acid type linkers were designed and synthesized for peptide derivatization in solid phase. Three of them were obtained in a crystalline form. The crystallized linkers can be stored at 4 degrees C for 2 years without significant decomposition. Protocols for biotinylation and fluorescent labeling of peptides in solid phase were developed. The linkers also provide good ionization ability for single-bead mass spectrometry analysis of peptides.

Biotinylation↗

PubMed2002

Identification of genes enriched in rice roots of the local nitrate treatment and their expression patterns in split-root treatment.

To identify nitrate-induced genes in rice roots, a nitrate-induced root subtracted library was constructed using the suppression subtractive hybridization (SSH) method and a split-root experiment. Based on forward and reverse screening, 37 known genes and 55 novel genes were identified to be up-regulated in nitrate-supplied side roots. The known genes are involved in nitrogen (N) uptake and assimilation, sugar transport and organic acid metabolism, signal transduction, protein synthesis and degradation, plant resistance, hormone metabolism and cell division. Most of these genes were stronger up-regulated in nitrate-supplied than in nitrate-deficient side roots, which suggests that nitrate may regulate expression of these genes. Expression pattern analysis also revealed that a fast cycle of assimilated N metabolites occurred between root and shoot. Transcriptions of some nitrate-induced genes were also up-regulated in nitrate-deficient side roots, which indicates that nitrate and/or in coordinating with N metabolites from shoots, regulate the transcription of many genes. The enhancement of carbon (C) source partition, the expressions of genes for signal transduction and transcription regulation, auxin transport and ethylene synthesis, and cyclin-dependent kinases may be responsible for the stimulated lateral root growth by nitrate.

Adaptation, Physiological↗

PubMedDate not supplied

Development of tissue plasminogen activator specific "on demand cleavable" (odc) linkers for radioimmunotherapy by screening one-bead-one-compound combinatorial peptide libraries.

New strategies are needed to protect normal organs from radiation in cancer radioimmunotherapy (RIT). This can be achieved by rapid clearance of radiometal in the circulation after accumulation of radioimmunoconjugates (RIC) in the tumor. Our strategy is to place highly efficient and specific cleavable linkers between radiometal chelates and the tumor targeting agents. Such linkers must be resistant to cleavage by enzymes present in the plasma and the tumor. After radiotargeting agents have accumulated in the tumor, a cleaving agent can be administered "on demand" to cleave a specific linker, resulting in the release of radiometal from the circulating RIC in a form that will have rapid renal clearance. We have selected TNKase, a thrombolytic agent approved for patient use, as our model on-demand cleaving agent. To identify TNKase-specific linkers, we screened fluorescent-quenched random "one-bead-one-compound" (OBOC) combinatorial peptide libraries. d-Amino acid containing peptides that were specific for TNKase but were resistant to cleavage by plasma and tumor-associated proteases were identified. One of these peptide substrates (rqYKYkf) was used to link the DOTA chelate to ChL6, a monoclonal antibody known to target breast cancer. This antibody conjugate was stable in plasma for 7 days while preserving the immunoreactivity to intact tumor cells. The addition of TNKase at clinical achievable plasma level (10 mug/mL) resulted in the release of 28% of the radiometal from the radioimmunoconjugate within 72 h. This lead linker, after further optimization to increase its response to TNKase, may be useful in the development of more effective radioimmunotherapeutic and radioimaging agents.

Cellulose↗

PubMedDate not supplied

Partial alloc-deprotection approach for ladder synthesis of "one-bead one-compound" combinatorial libraries.

The topologically segregated bilayer-bead concept has been applied to encoded "one-bead one-compound"(OBOC) combinatorial libraries to avoid the interference of coding tags with biological screening. In this paper, we report on the development of a novel partial Alloc-deprotection (PAD) approach and the use of this approach to establish a new ladder-synthesis method for OBOC combinatorial libraries to further exploit the concept. In the PAD approach, Alloc-protected beads are partially deprotected, sequentially layer by layer, starting from the outer layer toward the bead interior. The degree of deprotection (or thickness of each layer) is controlled by the time of exposure to the deprotecting agent, palladium. By repetitive use of the PAD approach, a small portion of Alloc-protected N termini in the bead interior is liberated in each synthetic cycle for generation of an additional ladder member such that each library bead will carry a full-length library compound on the bead surface and a series of truncated ladder members in the bead interior. For the libraries containing isobaric residues, a simple encoding strategy is introduced in the ladder-synthesis method so that the isobaric residues can be differentiated by the coding tags. One advantage of this encoding strategy is that the coding tags are confined together with the truncated ladder members in the bead interior, thus maintaining the arrangement that only the library compounds are displayed on the bead surface. The PAD approach of forming multiple concentric functional layers inside a bead is simple, reliable, and may have other applications in addition to OBOC combinatorial library bead encoding, such as the development of novel optically encoded beads for multiplex immunodiagnostics or even information recording.

Amino Acids↗