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Selective Mechanism (selective + mechanism)
Selected AbstractsA cremophor-free formulation for tanespimycin (17-AAG) using PEO- b -PDLLA micelles: Characterization and pharmacokinetics in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2009May P. Xiong Abstract Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L -lactide) (PEO- b -PDLLA). Dynamic light scattering revealed PEO- b -PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO- b -PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CLrenal) increased and the hepatic clearance (CLhepatic) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t1/2) of the drug in serum and 1.2-fold increase in t1/2 of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (Vd) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO- b -PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1577,1586, 2009 [source] Design of translactam HCMV protease inhibitors as potent antiviralsMEDICINAL RESEARCH REVIEWS, Issue 4 2005Alan D. Borthwick Abstract Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our ,Ala HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)-,-methyl pyrrolidine-5,5- trans -lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X-ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti-HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev. [source] Selection for a dominant oncogene and large male size as a risk factor for melanoma in the Xiphophorus animal modelMOLECULAR ECOLOGY, Issue 15 2010ANDRÉ A. FERNANDEZ Abstract Adult height is a risk factor in numerous human cancers that involve aberrant receptor tyrosine kinase (RTK) signalling. However, its importance is debated due to conflicting epidemiological studies and the lack of useful in vivo models. In Xiphophorus fishes (Platyfishes/Swordtails), a functional RTK, Xiphophorus melanoma receptor kinase (Xmrk), serves as the dominant oncogene and has been maintained for several million years despite being deleterious and in an extremely unstable genomic region. Here we show that the Xmrk genotype is positively correlated with standard length in male and female wild caught Xiphophorus cortezi sampled throughout their phylogeographic distribution. Histopathology confirms the occurrence of malignant melanomas in both sexes; however, melanoma incidence was extremely male biased. Furthermore, males collected with malignant melanomas in the field were significantly larger than both Xmrk males collected without melanomas and wildtype (Xmrk deficient) males. These results not only provide a novel selective mechanism for the persistence of the germline Xmrk oncogene but also create an innovative avenue of melanoma research within the Xiphophorus fishes. Wildlife cancer in natural systems is a growing concern, therefore, future research investigating life history characteristics associated with certain phenotypes and genotypes that predispose an individual to cancer will be fundamental to increasing our understanding of the evolutionary biology of cancer in nature as well as in humans. [source] Competition as a selective mechanism for larger offspring size in guppiesOIKOS, Issue 1 2008Farrah Bashey Highly competitive environments are predicted to select for larger offspring. Guppies Poecilia reticulata from low-predation populations have evolved to make fewer, larger offspring than their counterparts from high-predation populations. As predation co-varies with the strength of competition in natural guppy populations, here I present two laboratory experiments that evaluate the role of competition in selecting for larger offspring size. In the first experiment, paired groups of large and small newborns from either a high- or a low-predation population were reared in mesocosms under a high- or a low-competition treatment. While large newborns retained their size advantage over small newborns in both treatments, newborn size increased growth only in the high-competition treatment. Moreover, the increase in growth with size was greater in guppies derived from the low-predation population. In the second experiment, pairs of large and small newborns were reared in a highly competitive environment until reproductive maturity. Small size at birth delayed maturation and the effect of birth size on male age of maturity was greater in the low-predation population. These results support the importance of competition as a selective mechanism in offspring size evolution. [source] Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia,ANNALS OF NEUROLOGY, Issue 3 2009Anne Vaslin MSc Objective Targeting neuroprotectants specifically to the cells that need them is a major goal in biomedical research. Many peptidic protectants contain an active sequence linked to a carrier such as the transactivator of transcription (TAT) transduction sequence, and here we test the hypothesis that TAT-linked peptides are selectively endocytosed into neurons stressed by excitotoxicity and focal cerebral ischemia. Methods In vivo experiments involved intracerebroventricular injection of TAT peptides or conventional tracers (peroxidase, fluorescein isothiocyanate-dextran) in young rats exposed to occlusion of the middle cerebral artery at postnatal day 12. Cellular mechanisms of uptake were analyzed in dissociated cortical neuronal cultures. Results In both models, all tracers were taken up selectively into stressed neurons by endocytosis. In the in vivo model, this was neuron specific and limited to the ischemic area, where the neurons displayed enhanced immunolabeling for early endosomal antigen-1 and clathrin. The highly efficient uptake of TAT peptides occurred by the same selective mechanism as for conventional tracers. All tracers were targeted to the nucleus and cytoplasm of neurons that appeared viable, although ultimately destined to die. In dissociated cortical neuronal cultures, an excitotoxic dose of N -methyl- D -aspartate induced a similar endocytosis. It was 100 times more efficient with TAT peptides than with dextran, because the former bound to heparan sulfate proteoglycans at the cell surface, but it depended on dynamin and clathrin in both cases. Interpretation Excitotoxicity-induced endocytosis is the main entry route for protective TAT peptides and targets selectively the neurons that need to be protected. Ann Neurol 2009;65:337,347 [source] Active Site Ring-Opening of a Thiirane Moiety and Picomolar Inhibition of GelatinasesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2009Christopher Forbes (±)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable Ki of 530 pm against matrix metalloproteinase-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases. [source] Evolution and persistence of the ciliumCYTOSKELETON, Issue 12 2007Peter Satir Abstract The origin of cilia, a fundamental eukaryotic organelle, not present in prokaryotes, poses many problems, including the origins of motility and sensory function, the origins of nine-fold symmetry, of basal bodies, and of transport and selective mechanisms involved in ciliogenesis. We propose the basis of ciliary origin to be a self-assembly RNA enveloped virus that contains unique tubulin and tektin precursors. The virus becomes the centriole and basal body, which would account for the self-assembly and self-replicative properties of these organelles, in contrast to previous proposals of spirochaete origin or endogenous differentiation, which do not readily account for the centriole or its properties. The viral envelope evolves into a sensory bud. The host cell supplies the transport machinery and molecular motors to construct the axoneme. Polymerization of cytoplasmic microtubules in the 9 + 0 axoneme completes the 9 + 2 pattern. Cell Motil. Cytoskeleton 2007. © 2007 Wiley-Liss, Inc. [source] | |||||||||||||