Hybrid Amyloid-Based Redox Hydrogel for Bioelectrocatalytic H2 Oxidation.

An artificial amyloid-based redox hydrogel was designed for mediating electron transfer between a [NiFeSe] hydrogenase and an electrode. Starting from a mutated prion-forming domain of fungal protein HET-s, a hybrid redox protein containing a single benzyl methyl viologen moiety was synthesized. This protein was able to self-assemble into structurally homogenous nanofibrils. Molecular modeling confirmed that the redox groups are aligned along the fibril axis and are tethered to its core by a long, flexible polypeptide chain that allows close encounters between the fibril-bound oxidized or reduced redox groups. Redox hydrogel films capable of immobilizing the hydrogenase under mild conditions at the surface of carbon electrodes were obtained by a simple pH jump. In this way, bioelectrodes for the electrocatalytic oxidation of H2 were fabricated that afforded catalytic current densities of up to 270 µA cm-2 , with an overpotential of 0.33 V, under quiescent conditions at 45 °C.

Probing the helical forms of Ca2+ -guluronan junction zones in alginate gels by molecular dynamics 1: Duplexes.

A molecular dynamics investigation of the helical forms adopted by (1→4)-α-L-guluronan in explicit water environment was carried out. Single chains and duplexes were modeled at 300 K starting both from 21 or 32 helical conformations and in the presence of a neutralizing amount of Ca(2+) ions. All systems were allowed full conformational freedom. The initial perfect helices with integral screw symmetries were lost at the very beginning of simulations and two distinct behaviors were observed: At equilibrium the 21 models mostly retained the 21 local helical conformations while exploring the 32 ones the rest of the time. In duplexes the two chains, which behaved similarly, were well extended and slightly twisted. By contrast, the chains in 32 duplex models were dissimilar and explored a much broader conformational space in which 21 and 32 local helical conformations were dominant and equally represented but the 31 and other conformations were also present. The wide variety of conformations revealed in this study is consistent with the general difficulty in obtaining crystals of Ca(2+)-guluronate with suitable lateral dimensions for crystallographic studies.

Biohybrid glycopolymer capable of ionotropic gelation.

Ionotropic gelation is particularly appealing for the formation of hydrogels because it takes place under mild conditions, is not thermoreversible, and does not involve toxic chemicals. A well-known example is the gelation of alginate in the presence of calcium ions, which is at the base of numerous applications involving this polymer. In this study, alginate-derived oligosaccharides were converted into acrylamide- and methacrylamide-type macromonomers in two steps without resorting to protective group chemistry. They were then copolymerized with 2-hydroxyethylmethacrylamide in aqueous solution to yield high molar mass biohybrid glycopolymers containing between 25 and 52% by mass of oligosaccharide graft chains. A comparative kinetic study showed that both acrylamide- and methacrylamide-type macromonomers reacted since the early stages of the copolymerization, but that the mole fraction in the polymer was smaller than in the feed up to 50-60% conversion and increased markedly afterward. This effect was slighter for the methacrylamide-type macromonomer though. Copolymers carrying oligosaccharide chains with 16-20 repeating units were synthesized and used for a gelation experiment: When dialyzed against CaCl(2) 0.5 mol L(-1), the polymer carrying (1→4)-α-l-guluronan residues led to a soft isotropic self-standing transparent hydrogel, while the polymer carrying (1→4)-ß-d-mannuronan residues gave a loose opaque gel. This study demonstrates that alginate-extracted oligosaccharides and aqueous radical polymerization can be combined for the flexible design of biohybrid glycopolymers capable of ionotropic gelation under very mild conditions.

Pharmacoeconomic considerations for acute myeloid leukemia pharmacotherapy.

INTRODUCTION: Acute myeloid leukemia (AML) is a rare blood cancer with a poor prognosis. Recently, targeted drugs have improved survival both in the elderly and in fit patients. However, as monthly costs of targeted agents are high, regulatory bodies often impose restrictions on their use. AREAS COVERED: The authors review the value-for-cost of targeted drugs such as gemtuzumab ozogamycin, CPX-351, midostaurin, gilteritinib, glasdegib, venetoclax, oral azacytidine and enasidenib used to treat adult AML. EMBASE and TRIP databases, together with authority websites were searched for technology assessments. Add-on drugs, namely midostaurin and gemtuzumab ozogamycin, have been reported to have the best pharmacoeconomic profile for newly diagnosed fit patients with FLT3 mutation or favorable/intermediate cytogenetics, since allogeneic transplant rates were stable or reduced. Most of the other drugs, on the other hand, did not achieve highly favorable cost-for-benefit, due to a poor absolute survival gain and/or increased transplant rates. EXPERT OPINION: The cost of most targeted therapies for AML in unfit patients seems unfair in comparison to the absolute survival advantage provided in fit patients. Point of cure and transplant outcomes should be standardized to allow comparability among the models.

Inhibition of ice crystal growth by synthetic glycopolymers: implications for the rational design of antifreeze glycoprotein mimics.

A series of structurally diverse polymers, containing either peptide or vinyl-derived backbones, was tested for ice recrystallization inhibition activity, which is commonly associated with antifreeze (glyco)proteins. It was revealed that only polymers bearing hydroxyl groups in the side chain could inhibit ice growth. Furthermore, well-defined glycopolymers were shown to have a small but significant recrystallization inhibition effect, showing that it may be possible to design antifreeze glycoprotein mimics based upon polymers derived from vinyl monomers.

Facile in situ preparation of biologically active multivalent glyconanoparticles.

Biologically active multivalent glyconanoparticles are prepared in an extremely simple method by reduction of well-defined glycopolymers, prepared by RAFT polymerisation, in an aqueous solution of HAuCl(4).

Protecting-Group-Free Synthesis of Well-Defined Glycopolymers Featuring Negatively Charged Oligosaccharides.

Control of the macromolecular architecture is essential to enable sophisticated functions for glycopolymers and to allow a precise correlation between these functions and the polymer structure. A number of biologically important ligands are negatively charged oligosaccharides that are difficult to manipulate in organic solvent and that are hardly amenable to protection/deprotection strategies. RAFT polymerization is a simple and robust technique that enables the synthesis of well-defined glycopolymers directly in aqueous solution and starting from unprotected vinyl glycomonomers. Here I describe how RAFT polymerization can be combined with reductive amination to transform negatively charged oligosaccharides having 5-20 monosaccharide units into well-defined glycopolymers directly in water and without the need to resort to protecting-group chemistry.

Synthesis of ß-D-glucopyranuronosylamine in aqueous solution: kinetic study and synthetic potential.

A systematic study of the synthesis of ß-D-glucopyranuronosylamine in water is reported. When sodium D-glucuronate was reacted with ammonia and/or volatile ammonium salts in water a mixture of ß-D-glucopyranuronosylamine and ammonium N-ß-D-glucopyranuronosyl carbamate was obtained at a rate that strongly depended on the experimental conditions. In general higher ammonia and/or ammonium salt concentrations led to a faster conversion of the starting sugar into intermediate species and of the latter into the final products. Yet, some interesting trends and exceptions were observed. The use of saturated ammonium carbamate led to the fastest rates and the highest final yields of ß-D-glucopyranuronosylamine/carbamate. With the exception of 1 M ammonia and 0.6 M ammonium salt, after 24 h of reaction all tested protocols led to higher yields of ß-glycosylamine/carbamate than concentrated commercial ammonia alone. The mole fraction of α-D-glucopyranuronosylamine/carbamate at equilibrium was found to be 7-8% in water at 30°C. Concerning bis(ß-D-glucopyranuronosyl)amine, less than 3% of it is formed in all cases, with a minimum value of 0.5% in the case of saturated ammonium carbamate. Surprisingly, the reaction was consistently faster in the case of sodium D-glucuronate than in the case of D-glucose (4-8 times faster). Finally, the synthetic usefulness of our approach was demonstrated by the synthesis of three N-acyl-ß-D-glucopyranuronosylamines and one N-alkylcarbamoyl-ß-D-glucopyranuronosylamine directly in aqueous-organic solution without resorting to protective group chemistry.

Synthesis of well-defined glycopolymers and some studies of their aqueous solution behaviour.

Well-defined polymers with carbohydrate residues pendant to the main chain (glycopolymers) were prepared by reversible addition fragmentation chain transfer (RAFT) polymerisation. Excellent control over molecular weight and narrow polydispersities (1.1-1.2) were achieved over a range of molecular weights. In addition, efficient synthesis of block copolymers by sequential monomer addition with both hydrophilic and hydrophobic non-carbohydrate blocks was demonstrated. The aqueous solution behaviour of amphiphilic block glycopolymers was investigated, revealing the formation of multivalent carbohydrate-bearing aggregates in solution with the capability for the solubilisation of hydrophobic species (a water-insoluble dye). One such amphiphilic glycopolymer shows by TEM the formation of a worm-like micelle phase. Further investigations of these novel bioactive macromolecular assemblies are underway.

Chemoenzymatic synthesis of narrow-polydispersity glycopolymers: poly(6-O-vinyladipoyl-D-glucopyranose).

The glycomonomer 6-O-vinyladipoyl-D-glucopyranose was prepared via lipase catalyzed transesterification of divinyladipate with alpha-D-glucopyranose in dry acetonitrile and acetone. The desired 6-O regioisomer was obtained in good yield, and its structure was confirmed by correlation NMR spectroscopy. Controlled radical polymerization of the unprotected monomer was performed in protic media using both xanthate and dithiocarbamate as chain transfer agents to give poly(6-O-vinyladipoyl-D-glucopyranose) with Mn of 17 and 19 kDa (SEC) respectively and a polydispersity as low as 1.10. To the best of our knowledge, this is the first example of a narrow-polydispersity, poly(vinyl ester)-like glycopolymer.