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PubMed2005

Synthesis of a novel galactosylated lipid and its application to the hepatocyte-selective targeting of liposomal doxorubicin.

This paper described the synthesis of a novel galactosylated lipid with mono-galactoside moiety, (5-Cholesten-3beta-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate (CHS-ED-LA), and the targetability of doxorubicin (DOX), a model drug, in liposomes containing 10% mol/mol CHS-ED-LA (galactosylated liposomes, GalL) to the liver was studied. The weighted-average overall drug targeting efficiency (Te(*)) was used to evaluate the liver targetability of GalL DOX. The results showed that GalL DOX gave a relatively high (Te(*))(liver) value of 64.6%, while DOX in conventional liposome (CL DOX) only gave a (Te(*))(liver) value of 21.8%. In the liver, the GalL DOX was mainly taken up by parenchymal cells (88% of the total hepatic uptake). Moreover, preinjection of asialofetuin significantly inhibited the liver uptake of GalL DOX (from 70 to 12% of the total injected dose). It was suggested that liposomes containing such novel galactosylated lipid, CHS-ED-LA, had a great potential as drug delivery carriers for hepatocyte-selective targeting.

Animals↗
PubMed1998

Anti-HIV agents that selectively target retroviral nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins.

Agents that target the two highly conserved Zn fingers of the human immunodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under development as antivirals. These agents covalently modify Zn-coordinating cysteine thiolates of the fingers, causing Zn ejection, loss of native protein structure and nucleic acid binding capacity, and disruption of virus replication. Concentrations of three antiviral agents that promoted in vitro Zn ejection from NCp7 and inhibited HIV replication did not impact the functions of cellular Zn finger proteins, including poly(ADP-ribose) polymerase and the Sp1 and GATA-1 transcription factors, nor did the compounds inhibit HeLa nuclear extract mediated transcription. Selectivity of interactions of these agents with NCp7 was supported by molecular modeling analysis which (1) identified a common saddle-shaped nucleophilic region on the surfaces of both NCp7 Zn fingers, (2) indicated a strong correspondence between computationally docked positions for the agents tested and overlap of frontier orbitals within the nucleophilic loci of the NCp7 Zn fingers, and (3) revealed selective steric exclusion of the agents from the core of the GATA-1 Zn finger. Further modeling analysis suggests that the thiolate of Cys49 in the carboxy-terminal finger is the site most susceptible to electrophilic attack. These data provide the first experimental evidence and rationale for antiviral agents that selectively target retroviral nucleocapsid protein Zn fingers.

Animals↗
PubMed1999

Computer-aided target selection-prioritizing targets for antifungal drug discovery.

The entire DNA sequence of the Saccharomyces cerevisiae genome was completed in 1996 and represents the first entirely decoded eukaryotic genome. Because major human pathogenic fungi such as Candida albicans are closely related to S. cerevisiae on a molecular level, the question arises as to how this new information can be used to identify and prioritize those genes that are most suitable as targets for antimycotic drug discovery. To tackle this challenge, a software tool called CATS (computer-aided target selection) was developed. The authors describe how it allows an automated and periodically updated assessment of all S. cerevisiae genes to be carried out with regard to their suitability as antifungal targets.

Journal Article↗
PubMed2000

Target selectivity of bicoid is dependent on nonconsensus site recognition and protein-protein interaction.

We describe experiments to compare the activities of two Drosophila homeodomain proteins, Bicoid (Bcd) and an altered-specificity mutant of Fushi tarazu, Ftz(Q50K). Although the homeodomains of these proteins share a virtually indistinguishable ability to recognize a consensus Bcd site, only Bcd can activate transcription from natural enhancer elements when assayed in both yeast and Drosophila Schneider S2 cells. Our analysis of chimeric proteins suggests that both the homeodomain of Bcd and sequences outside the homeodomain contribute to its ability to recognize natural enhancer elements. We further show that, unlike the Bcd homeodomain, the Ftz(Q50K) homeodomain fails to recognize nonconsensus sites found in natural enhancer elements. The defect of a chimeric protein containing the homeodomain of Ftz(Q50K) in place of that of Bcd can be preferentially restored by converting the nonconsensus sites in natural enhancer elements to consensus sites. Our experiments suggest that the biological specificity of Bcd is determined by combinatorial contributions of two important mechanisms: the nonconsensus site recognition function conferred by the homeodomain and the cooperativity function conferred primarily by sequences outside the homeodomain. A systematic comparison of different assay methods and enhancer elements further suggests a fluid nature of the requirements for these two Bcd functions in target selection.

Animals↗
PubMed2001

Assembly and clustering of acetylcholine receptors containing GFP-tagged epsilon or gamma subunits: selective targeting to the neuromuscular junction in vivo.

Acetylcholine receptor (AChR) gamma and epsilon subunits were tagged by green fluorescent protein (GFP) to analyse assembly and targeting in live muscle fibers at the neuromuscular junction. N- or C-terminal fusion polypeptides showed no fluorescence upon transfection of HEK cells. When GFP was inserted into the cytoplasmic loop connecting putative transmembrane regions M3 and M4, the gamma/GFP and epsilon/GFP subunits were fluorescent and formed together with the alpha, beta, and delta subunits GFP-tagged AChR complexes that were integrated into the plasma membrane. As the AChR were also clustered by rapsyn, the results indicate that the cytoplasmatic domains of the gamma and epsilon subunits may not be required for assembly and rapsyn-dependent clustering. The gamma/GFP and epsilon/GFP subunit-containing receptors were expressed in X. laevis oocytes and have affinities for acetylcholine similar to that of the wild-type receptors. Direct gene transfer into single muscle fibers reveals that gamma/GFP or epsilon/GFP polypeptides are expressed at the site of injection and are transported within the endoplasmatic reticulum. When reaching subsynaptic regions, both gamma/GFP or epsilon/GFP subunits compete with endogenous epsilon subunits to assemble GFP-tagged receptors, which are selectively targeted to the postsynaptic membrane.

Animals↗
PubMed2005

A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.

Animals↗
PubMed1986

Altered methylation complex isozymes as selective targets for cancer chemotherapy.

MC2 is a ternary enzyme complex consisting of MAT, methyltransferase and SAHH. Three isozymes of SAHH have been identified from rat and mouse livers based on different kinetic properties. The Km values are 0.35 +/- 0.05 microM, 1.63 +/- 0.38 microM and 0.37 +/- 0.07 mM for SAHH-L, SAHH-I, and SAHH-H respectively. The corresponding low Km isozymes of MAT and SAHH form MCs-L which include RNA MCs, the intermediate Km isozymes form MC-I, and the high Km isozymes form MC-H which is glycine MC. MCs-L are common to all tissues whereas MC-I and MC-H are organ specific enzyme complexes. Low levels of MC-H in the liver of C3H/HeN mouse are correlated with the slow maturation of hepatocytes and the genetic predisposition to develop spontaneous PHC. Rat Novikoff ascites hepatoma and mouse spontaneous PHC have been shown to contain a SAHH isozyme displaying kinetic properties different from the corresponding normal SAHH-L. The abnormal kinetic properties of tumour SAHH are analogous to those of tumour MAT previously shown by the authors to be uniquely associated with malignant tissues. The tumour isozyme, which is named SAHH-LT, has a Km (AR) value of 2.18 +/- 0.22 microM. The altered tumour MC isozymes appear to play an important role in perpetuating malignant growth, because once the tumour growth was inhibited by poly (I) (C), the abnormal kinetic properties were no longer detectable. Thus abnormal tumour MCs may be exploited as selective targets for cancer chemotherapy. Evidence is presented to indicate that antineoplaston is a potent inhibitory effector of tumour rRNA MCs and an effective antitumor agent.

Adenosylhomocysteinase↗
PubMed2001

Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes.

BACKGROUND: Psoriatic plaques are characterized by infiltration with CD4+ CD45RO+ and CD8+ CD45RO+ memory effector T lymphocytes. The recombinant protein alefacept binds to CD2 on memory effector T lymphocytes, inhibiting their activation. METHODS: In a multicenter, randomized, placebo-controlled, double-blind study, we evaluated alefacept as a treatment for psoriasis. Two hundred twenty-nine patients with chronic psoriasis received intravenous alefacept (0.025, 0.075, or 0.150 mg per kilogram of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks. Before treatment, the median scores on the psoriasis area-and-severity index were between 14 and 20 in all groups (0 denotes no psoriasis and 72 the most severe disease possible). RESULTS: Alefacept was well tolerated and nonimmunogenic. The mean reduction in the score on the psoriasis area-and-severity index two weeks after treatment was greater in the alefacept groups (38, 53, and 53 percent in the groups receiving 0.025, 0.075, and 0.150 mg per kilogram, respectively) than in the placebo group (21 percent, P<0.001). Twelve weeks after treatment, 28 patients who had received alefacept alone were clear or almost clear of psoriasis. Three patients in the placebo group were clear or almost clear; all three had received additional systemic therapy for psoriasis. Alefacept reduced peripheral-blood memory effector T-lymphocyte (CD45RO+) counts, and the reduction in the number of memory-effector T lymphocytes was correlated with the improvement in psoriasis. CONCLUSIONS: Treatment with alefacept for 12 weeks is associated with improvement in chronic plaque psoriasis; some patients have a sustained clinical response after the cessation of treatment. Alefacept selectively targets CD45RO+ memory effector T lymphocytes, suggesting that they have a role in the pathogenesis of psoriasis.

Adjuvants, Immunologic↗
PubMed1994

Epidermal growth factor receptors in human breast carcinoma cells: a potential selective target for transforming growth factor alpha-Pseudomonas exotoxin 40 fusion protein.

Epidermal growth factor (EGF) receptors are expressed in high levels by some poor prognosis breast tumors. We have examined the cytotoxic effect of the tumor growth factor alpha (TGF alpha)-delta Cys-Pseudomonas exotoxin (PE40) recombinant fusion protein on normal and tumorigenic human breast epithelial cells in vitro and in vivo. The MDA-468, MDA-231, BT-20, and MCF-7ADR estrogen receptor-negative, EGF receptor-rich breast cancer lines were exquisitely sensitive in vitro to TGF alpha-delta Cys-PE40 with a 50% inhibitory concentration of < or = 0.02 nM. The estrogen receptor-positive, low EGF receptor MCF-7, ZR75-1, and T47D cells were less sensitive to the fusion toxin with a 50% inhibitory concentration of > 0.2 nM. The nontumorigenic cell lines 184, 184A1, and 184B5 were relatively resistant to TGF alpha-delta Cys-PE40 despite exhibiting high levels of EGF receptors. Continuous i.p. administration of TGF alpha-delta Cys-PE40 via an osmotic minipump at a dose of 0.4 microgram/g/day over 7 days inhibited MDA-468, MA-231, and BT-20 but not MCF-7 tumor growth in female athymic mice. Host tissue toxicity was not observed with this dose of TGF alpha-delta Cys-PE40. Mixed MDA-468/MCF-7 tumors were established in nude mice after coinoculation of both cell types in estrogen-supplemented animals. EGF receptor immunohistochemistry and immunoblot procedures indicated that TGF alpha-PE40 eliminated the MDA-468 cells while sparing the adjacent MCF-7 cells. By immunoblot, EGF receptors were consistently more abundant in tumor tissue than in adjacent nontumor tissue from the same mastectomy specimen (n = 7). These data support the notion that EGF receptors can be selectively targeted in human breast cancer cells for the delivery of antitumor agents. Further clinical studies with TGF alpha-delta Cys-PE40 and other chimeric toxins using the same cellular target will address this possibility.

Animals↗
PubMedDate not supplied

Assessment of the radiochemical design of antibodies with a metabolizable linkage for target-selective radioactivity delivery.

Interposition of a metabolizable linkage has been performed to reduce the hepatic radioactivity levels of radiolabeled antibodies. To estimate the validity of this strategy, a radioiodination reagent (HML) that provides a stable attachment for m-iodohippuric acid with proteins in plasma while facilitating rapid and selective release of the compound after lysosomal proteolysis in the liver was conjugated with a monoclonal antibody (mAb) against osteogenic sarcoma (OST7, IgG1). Radiolabeled OST7 conjugates with a plasma-labile ester bond for releasing m-iodohippuric acid (MIH), plasma-stable amide bonds for releasing radiometabolites of hepatobiliary excretion (MPH), or slow elimination rates from hepatocytes ([111In]EMCS-Bz-EDTA) were prepared with similar conjugation chemistry. The four radiolabeled OST7 conjugates were characterized both in vitro and in vivo. All the radiolabeled OST7 conjugates had similar radiochromatograms on size-exclusion HPLC and similar antigen binding affinities. While MIH-OST7 indicated accelerated clearance of radioactivity from the blood due to the release of m-iodohippurate, the rest of the three radiolabeled OST7 conjugates remained stable in serum incubation studies and had similar radioactivity elimination from the blood in vivo. When injected into normal mice, HML-OST7 demonstrated tissue-to-blood ratios of radioactivity similar to those of MIH-OST7 and significantly lower than those of the other two radiolabeled OST7 conjugates. In biodistribution studies in nude mice, both HML-OST7 and MIH-OST7 exhibited tumor-to-liver or tumor-to-intestine ratios of radioactivity higher than those of [111In]EMCS-Bz-EDTA-OST7 or MPH-OST7, respectively. HML-OST7, MPH-OST7, and [111In]EMCS-Bz-EDTA-OST7 indicated there were no changes in the radioactivity levels in the tumor between 24 and 48 h postinjection, whereas MIH-OST7 significantly decreased the radioactivity levels in the tumor at these time points. HML reduced the radioactivity levels in nontarget tissues without impairing the tumor radioactivity levels delivered by OST7. These findings indicated that the design of a radiolabeled mAb that is stable in plasma and liberates the radiometabolite of rapid urinary excretion constitutes an effective strategy for achieving target-selective radioactivity delivery.

Animals↗
PubMed2000

Methodologies for target selection in structural genomics.

As the number of complete genomes that have been sequenced keeps growing, unknown areas of the protein space are revealed and new horizons open up. Most of this information will be fully appreciated only when the structural information about the encoded proteins becomes available. The goal of structural genomics is to direct large-scale efforts of protein structure determination, so as to increase the impact of these efforts. This review focuses on current approaches in structural genomics aimed at selecting representative proteins as targets for structure determination. We will discuss the concept of representative structures/folds, the current methodologies for identifying those proteins, and computational techniques for identifying proteins which are expected to adopt new structural folds.

Databases, Factual↗
PubMed1998

Neurotransmitters and neurodevelopment. Role of dopamine in neurite outgrowth, target selection and specific synapse formation.

Neurotransmitters and their receptors appear early during nervous system development and are thought to play important roles in neurite outgrowth, growth cone motility, target cell selection and synaptogenesis. In vivo studies in both vertebrates and invertebrates have shown that the perturbations of embryonic transmitter expression result in abnormal morphological and synaptic development. In vitro studies have further revealed that transmitters are capable of affecting neurite outgrowth and growth cone behaviour. The precise cellular mechanisms by which neurotransmitters affect these developmental steps are, however, poorly defined. In vitro, a presynaptic neuron from the mollusc Lymnaea stagnalis releases dopamine, which induces both growth cone attraction and growth cone collapse of target and non-target cell growth cones, respectively. We propose that the ability of dopamine to differentially affect growth cone motility of two cell types results from a divergence of the dopamine receptor-activated second messenger pathways at the G-protein level. Such transmitter-receptor interactions between growth cones of specific neurons may not only induce changes in the growth cone motility, but may subsequently play an important role in target cell selection and specificity of synaptogenesis.

Animals↗
PubMed2006

Target selection and deselection at the Berkeley Structural Genomics Center.

At the Berkeley Structural Genomics Center (BSGC), our goal is to obtain a near-complete structural complement of proteins in the minimal organisms Mycoplasma genitalium and M. pneumoniae, two closely related pathogens. Current targets for structure determination have been selected in six major stages, starting with those predicted to be most tractable to high throughput study and likely to yield new structural information. We report on the process used to select these proteins, as well as our target deselection procedure. Target deselection reduces experimental effort by eliminating targets similar to those recently solved by the structural biology community or other centers. We measure the impact of the 69 structures solved at the BSGC as of July 2004 on structure prediction coverage of the M. pneumoniae and M. genitalium proteomes. The number of Mycoplasma proteins for which the fold could first be reliably assigned based on structures solved at the BSGC (24 M. pneumoniae and 21 M. genitalium) is approximately 25% of the total resulting from work at all structural genomics centers and the worldwide structural biology community (94 M. pneumoniae and 86 M. genitalium) during the same period. As the number of structures contributed by the BSGC during that period is less than 1% of the total worldwide output, the benefits of a focused target selection strategy are apparent. If the structures of all current targets were solved, the percentage of M. pneumoniae proteins for which folds could be reliably assigned would increase from approximately 57% (391 of 687) at present to around 80% (550 of 687), and the percentage of the proteome that could be accurately modeled would increase from around 37% (254 of 687) to about 64% (438 of 687). In M. genitalium, the percentage of the proteome that could be structurally annotated based on structures of our remaining targets would rise from 72% (348 of 486) to around 76% (371 of 486), with the percentage of accurately modeled proteins would rise from 50% (243 of 486) to 58% (283 of 486). Sequences and data on experimental progress on our targets are available in the public databases TargetDB and PEPCdb.

Amino Acids↗
PubMed2004

Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA.

PMR1 is a polysome-associated mRNA endonuclease that initiates the destabilization of albumin mRNA. The current study examined whether endonuclease-mediated mRNA decay involved the selective binding of PMR1 to substrate mRNA on polysomes. PMR1 is uniformly distributed throughout the cytoplasm on polysomes and in lighter complexes and does not colocalize in cytoplasmic foci with Dcp1. Deletion mutagenesis identified polysome-targeting domains in the N and C termini of PMR1, either of which could target GFP to polysomes. Selectivity in targeting to polysome-bound substrate mRNP was determined by testing the ability of full-length PMR1 or protein lacking targeting domains to recover albumin and luciferase mRNA from dissociated polysomes. Only PMR1 bearing intact polysome-targeting domains selectively recovered albumin mRNA, and polysome targeting of both protein and substrate was required for the efficient degradation of albumin mRNA. Thus, endonuclease-mediated mRNA decay occurs on a polysome-bound complex containing PMR1 and its substrate mRNA.

ATP-Binding Cassette Transporters↗
PubMed2004

Tumor-selective targeted delivery of genes and antisense oligodeoxyribonucleotides via the folate receptor.

Gene therapy is a promising approach for the treatment of cancer. The main obstacle for the clinical application of cancer gene therapy is the lack of gene transfer vectors that are safe, efficacious, and tumor-selective. In recent years, targeted gene delivery through cellular receptors, using either viral or nonviral vectors, is emerging as a novel approach to enhance the efficacy of tumor-selective gene delivery. The folate receptor (FR), which is absent in most normal tissues and elevated in over 90% of ovarian carcinomas and at a high frequency in other human malignancies, is an attractive tumor-selective target. FR-targeted vectors include folate-derivatized adenoviruses, cationic polymers, cationic liposomes, and pH-sensitive liposomes. In addition, FR-targeted liposomes have been evaluated for the targeted delivery of antisense oligodeoxyribonucleotides (ODNs). These vectors have invariably shown impressive FR-selectivity in cell culture assays and, in addition, shown promising tumor-specific gene transfer activity in several in vivo models. There are important theoretical advantages for FR-targeted vectors over traditional non-targeted vectors in therapeutic gene and oligodeoxyribonucleotides delivery in vivo to cancer cells. Further preclinical characterization of these vectors is, therefore, warranted to determine their potential utility in cancer gene therapy.

Animals↗
PubMed2001

Glial cells aid axonal target selection.

A key problem in developmental neurobiology is how axons home in on their correct target tissue and establish the correct synaptic contacts. Recent work shows that in the developing Drosophila visual system a population of distinct lamina glial cells ensures correct target layer selection of retinal axons. In the absence of lamina neurons, photoreceptor axons terminate their growth in the correct zone, but when glial cell migration into the lamina is disrupted, as in nonstop mutants, growth cones advance into deeper layers of the brain.

Animals↗
PubMed2004

Biodistribution characteristics of galactosylated emulsions and incorporated probucol for hepatocyte-selective targeting of lipophilic drugs in mice.

PURPOSE: Galactosylated emulsions containing cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing device" were developed for hepatocyte-selective drug targeting. The targeting efficiency of galactosylated emulsions was evaluated by a distribution study in mice. METHODS: Soybean oil/EggPC/cholesterol (Chol) (weight ratio, 70:25: 5) (bare) emulsions and soybean oil/EggPC/Gal-C4-Chol (weight ratio, 70:25:5) (Gal) emulsions were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [14C]probucol as a model lipophilic drug was incorporated in the emulsions or EggPC/Chol/Gal-C4-Chol (Gal) liposomes. Their tissue and intrahepatic distribution were evaluated following intravenous injection in mice. RESULTS: After intravenous injection, Gal-emulsions were rapidly eliminated from the blood and accumulated in the liver, in contrast to the bare-emulsions. The liver uptake clearance of Gal-emulsions was 3.2- and 1.2-times greater than that of bare-emulsions and Gal-liposomes, respectively. The uptake ratio in liver parenchymal cells (PC) and nonparenchymal cells (NPC) of Gal-emulsions was higher than that of Gal-liposomes, being 7.4 and 3.0, suggesting that Gal-emulsions are an effective PC-selective carrier. The hepatic uptake of Gal-emulsions, but not that of bare-emulsions, was significantly inhibited by the pre-dosing of not only lactoferrin but also Gal-liposomes, suggesting asialoglycoprotein receptor-mediated endocytosis. Furthermore, [14C]probucol incorporated in Gal-emulsions was efficiently delivered to the liver compared with Gal-liposomes. CONCLUSION: Gal-emulsions have been proven to be an alternative carrier for hepatocyte-selective drug targeting.

Animals↗