Galectin-3 is unique among the galectin family of animal lectins in its biological activities and structure. Most members of the galectin family including galectin-1 possess apoptotic activities, ...whereas galectin-3 possesses anti-apoptotic activity. Galectin-3 is also the only chimera type galectin and consists of a nonlectin N-terminal domain and a C-terminal carbohydrate-binding domain. Recent sedimentation equilibrium and velocity studies show that murine galectin-3 is a monomer in the absence and presence of LacNAc, a monovalent sugar. However, quantitative precipitation studies in the present report indicate that galectin-3 precipitates as a pentamer with a series of divalent pentasaccharides with terminal LacNAc residues. Furthermore, the kinetics of precipitation are fast, on the order of seconds. This indicates that although the majority of galectin-3 in solution is a monomer, a rapid equilibrium exists between the monomer and a small percentage of pentamer. The latter, in turn, precipitates with the divalent oligosaccharides, resulting in rapid conversion of monomer to pentamer by mass action equilibria. Mixed quantitative precipitation experiments and electron microscopy suggest that galectin-3 forms heterogenous, disorganized cross-linking complexes with the multivalent carbohydrates. This contrasts with galectin-1 and many plant lectins that form homogeneous, organized cross-linked complexes. The results are discussed in terms of the biological properties of galectin-3.
Within the framework of the fractional-dimensional space approach, the binding energy and the effective mass of a polaron confined in a GaAs film deposited on the AlxGa1−xAs substrate for different ...aluminum concentration at different values of substrate thickness are investigated. Analytical expressions allowing a very simple estimation of the corresponding polaron binding energy and mass shift are found. As functions of the film thickness, the numerical results for the polaron binding energy and mass shift in the GaAs film deposited on the AlxGa1−xAs substrate structure are obtained. Our calculations show that the polaron binding energy and mass shift both have their maxima in a GaAs film deposited on the AlxGa1−xAs substrate. It is shown that the polaron binding energy and mass shift for different aluminum concentration have a maximum at a certain film thickness for the sample with a given substrate thickness.
An efficient and practical post-processing technique based on reverse reconciliation for continuous variable quantum key distribution is proposed and simulated with low-density parity check (LDPC) ...codes. MultiLevel Coding/MultiStage Decoding, which fully utilizes optimization technique such as vector quantization and iterative decoding and the optimal channel coding most close to the Shannon limit, was used to realize efficient reverse reconciliation algorithm. Simulation results showed that the proposed method can improve the secure key distribution rate to 2.2 kb/s and the coding efficiency to 0.89 over 20 km in single-mode optical fiber. Moreover, there still is room for much improvement.
PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal ...relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.
Within the framework of the fractional-dimensional space approach, the binding energy and the effective mass of a polaron confined in a GaAs film deposited on the Al(x)Ga(1-x) As substrate for ...different aluminum concentration at different values of substrate thickness are investigated. Analytical expressions allowing a very simple estimation of the corresponding polaron binding energy and mass shift are found. As functions of the film thickness, the numerical results for the polaron binding energy and mass shift in the GaAs film deposited on the Al(x)Ga(1-x) As substrate structure are obtained. Our calculations show that the polaron binding energy and mass shift both have their maxima in a GaAs film deposited on the Al(x)Ga(1-x) As substrate. It is shown that the polaron binding energy and mass shift for different aluminum concentration have a maximum at a certain film thickness for the sample with a given substrate thickness.
In the past ten years, with the emergency of multivalent neoglycoconjugates such as glycopolymers, glycodendrimers, and glycoclusters, carbohydrates have gained a lot of attention in the hope of ...developing potent carbohydrate-based therapeutics, as well as the opportunities to investigate glycobiology.
So far many strategies have been explored to effectively assemble multivalent neoglycoconjugates. This work contains a discussion of the design and transition metal-mediated synthesis of terminal galactoside-carrying glycoclusters and glycodendrimers in detail.
Propargyl alpha-galactoside antigen monomer was synthesized using conventional glycosidation methods. Then analogues of alpha-galactoside antigen clusters were prepared utilizing the Sonogashira reaction as the key step. Various conditions for the Sonogashira have been investigated and an interesting finding is that this reaction does occur with Cu (I). These synthetic alpha-galactoside antigens have shown enhanced binding affinity toward human anti-alpha-galactoside antigen antibodies in biochemical assays.
Likewise, galactoclusters were prepared as potential galectin inhibitors. However, these fully deprotected compounds were barely soluble in aqueous conditions. To solve this problem, analogues of lactoclusters, having an extra glucosyl residue, with various valencies and structural features were synthesized. Kinetic precipitation tests demonstrated that most lactoclusters cross-linked with galectin-3 formed insoluble complexes quickly and this phenomenon was observed for the first time, thus suggesting the clustering of the receptors upon contact.
A sequence of olefin cross-metathesis, Sonogashira reaction, and cyclotrimerization was performed to assemble a hexameric C-linked glycopeptidomemetic.
Olefin cross-metathesis mediated by the second generation Grubbs catalyst was successfully effected to prepare extended glycoallyl halides and unnatural amino acids. These glycoallyl halides were proven to be useful in the synthesis of high order glycoclusters.
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Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral ...agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.
The interplay of mammalian lectins such as galectins with cellular glycoconjugates is intimately involved in crucial reaction pathways including tumor cell adhesion, migration or growth regulation. ...These clinically relevant functions explain the interest in designing glycoclusters with potent activity to interfere with lectin binding. In view of the perspective for medical applications the following objective arises: to correlate topological factors of ligand display most favorably to reactivity against endogenous lectins. To date, plant agglutinins have commonly been used as models. Properly addressing this issue we first prepared di- to tetravalent clusters from 2-propynyl lactoside under mild oxidative homocoupling conditions and using the Sonogashira palladium-catalyzed cross-coupling reaction with triiodobenzene or pentaerythritol cores. These products were tested for bioactivity in a competitive solid-phase assay using different labeled sugar receptors as probes, i,e. the beta-trefoil mistletoe lectin, the natural lactoside-binding immunoglobulin G fraction from human serum and three mammalian galectins from two subgroups. The lactose headgroups in the derivatives retained ligand properties. Differences in inhibitory capacity were marked between the galectins. In contrast to homodimeric proto-type galectins-1 and -7 significant inhibition of galectin-3 binding with a 7-fold increase in relative potency was observed for the trivalent compound. In comparison, the binding of the beta-trefoil mistletoe agglutinin was reduced best by tetravalent substances The result for galectin-3 was independently confirmed by haemagglutination and cytofluorometric cell binding assays. These data underline the feasibility of galectin-type target selectivity by compound design despite using an identical headgroup (lactose) in synthesis.
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The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that ...include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.
The binding energy and effective mass of a polaron in a GaAs film deposited on the Al0.3Ga0.7As substrate are studied theoretically by using the fractional-dimensional space approach. Our ...calculations show that the polaron binding energy and mass shift decrease monotonously with increasing the film thickness. For the film thicknesses with Lw ≤ 70Å and the substrate thicknesses with Lb ≤ 200Å, the different values of the substrate thickness influence the polaron binding energy and mass shift in the GaAs film. The polaron binding energy and mass shift increase monotonously with increasing the substrate thickness. For the film thickness with Lw ≥ 70Å or the substrate thicknesses with Lb ≤ 200Å, the different values of the substrate thickness have no significant influence on the polaron binding energy and mass shift in the GaAs film deposited on the Al0.3Ga0.7As substrate.
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