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Protein aggregation in biotherapeutics has been identified to increase immunogenicity, leading to immune-mediated adverse effects, such as severe allergic responses including anaphylaxis. The induction of anti-drug antibodies (ADAs) moreover enhances drug clearance rates, and can directly block therapeutic function. In this review, identified immune activation mechanisms triggered by protein aggregates are discussed, as well as physicochemical properties of aggregates, such as size and shape, which contribute to immunogenicity. Furthermore, factors which contribute to protein stability and aggregation are considered. Lastly, with these factors in mind, we encourage an innovative and multidisciplinary approach with regard to further research in the field, with the overall aim to avoid immunogenic aggregation in future drug development., Protein aggregation of biotherapeutics increases their immunogenicity, leading to immune-mediated adverse effects. In this review we discuss immune activation pathways, causes of aggregation and mitigation strategies.

Real-timetracking of pro drug up take, delivery and activation in vivore presents a major challenge for prodrug development. Here in, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimag-ing, offering unique insight into the prodrug pharmaco kinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach.

International audience; Surface modification of electrodes with glycans was investigated as a strategy for modulating the development of electrocatalytic biofilms for microbial fuel cell applications. Covalent attachment of phenyl-mannoside and phenyl-lactoside adlayers on graphite rod electrodes was achieved via electrochemically assisted grafting of aryldiazonium cations from solution. To test the effects of the specific bio-functionalities, modified and unmodified graphite rods were used as anodes in two-chamber microbial fuel cell devices. Devices were set up with wastewater as inoculum and acetate as nutrient and their performance, in terms of output potential (open circuit and 1 kΩ load) and peak power output, was monitored over two months. The presence of glycans was found to lead to significant differences in startup times and peak power outputs. Lactosides were found to inhibit the development of biofilms when compared to bare graphite. Mannosides were found, instead, to promote exoelectrogenic biofilm adhesion and anode colonization, a finding that is supported by quartz crystal microbalance experiments in inoculum media. These differences were observed despite both adlayers possessing thickness in the nm range and similar hydrophilic character. This suggests that specific glycan-mediated bioaffinity interactions can be leveraged to direct the development of biotic electrocatalysts in bioelectrochemical systems and microbial fuel cell devices.

International audience; Grafting of aryldiazonium cations bearing a p-mannoside functionality over microbial fuel cell (MFC) anode materials was performed to investigate the ability of aryl-glycoside layers to regulate colonisation by biocatalytic biofilms. Covalent attachment was achieved via spontaneous reactions and via electrochemically-assisted grafting using potential step experiments. The effect of different functionalisation protocols on MFC performance is discussed in terms of changes in wettability, roughness and electrochemical response of modified electrodes. Water contact angle measurements (WCA) show that aryl-mannoside grafting yields a significant increase in hydrophilic character. Surface roughness determinations via atomic force microscopy (AFM) suggest a more disordered glycan adlayer when electrografting is used to facilitate chemisorption. MFCs were used as living sensors to successfully test the coated electrodes the response of the MFCs in terms of start-up time was accelerated when compared to that of MFC equipped with non-modified electrodes, this suggests a faster development of a mature biofilm community resulting from aryldiazonium modifications, as confirmed by cyclic voltammetry of MFC anodes. These results therefore indicate that modification with glycans offers a bioinspired route to accelerating biofilm colonisation without any adverse effects on final MFC outputs.

Radical thiol-ene chemistry has been demonstrated for a range of applications in peptide science, including macrocyclisation, glycosylation and lipidation amongst a myriad of others. The thiol-ene reaction offers a number of advantages in this area, primarily those characteristic of “click” reactions. This provides a chemical approach to peptide modification that is compatible with aqueous conditions with high orthogonality and functional group tolerance. Additionally, the use of a chemical approach for peptide modification affords homogeneous peptides, compared to heterogeneous mixtures often obtained through biological methods. In addition to peptide modification, thiol-ene chemistry has been applied in novel approaches to biological studies through synthesis of mimetics and use in development of probes. This review will cover the range of applications of the radical-mediated thiol-ene reaction in peptide and protein science.

S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation. It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines. Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation. As the field develops, this chemistry will play a central role in our molecular understanding of Biology., The conversion of thioesters to amides via acyl transfer has become one of the most important synthetic techniques for the chemical synthesis and modification of proteins. This review discusses this S-to-N acyl transfer process, and highlights some of the key applications across chemistry and biology.

Carbon nano-onions (CNOs) possess favorable properties that make them suitable for biomedical applications, including their small size, ready surface modification, and good biocompatibility. Here, we report the covalent immobilization of a synthetic glycopeptide and the protein bovine serum albumin (BSA) onto the surface of carbon nano-onions using the maleimide&ndash, thiol &ldquo, addition reaction&rdquo, The glycopeptide and BSA are readily transported inside different cell lines, together with carbon nano-onions, through the endocytosis pathway. Our results show that carbon nano-onions are excellent scaffolds for glycopeptides and proteins immobilization and act as intracellular carriers for these biomolecules. These findings open new perspectives in the application of carbon nano-onions as intracellular transporters in diverse biomedical applications.

Correction for ‘Glycosylated naphthalimides and naphthalimide Tröger's bases as fluorescent aggregation probes for Con A’ by Elena Calatrava-Pérez et al., Org. Biomol. Chem., 2019, DOI: 10.1039/c8ob02980f.

A mild, inexpensive, and general photocatalytic initiation protocol for anti-Markovnikov hydrothiolation of olefins using carbon nanomaterial/metal oxide (carbon NM-MO) composites is reported. Graphene oxide (GO), nanodiamonds (ND), and carbon nano-onions (CNO) displaying bismuth or tungsten oxide nanoparticles adhered to the surface and function as highly efficient photocatalysts for thiol–ene ligation under both UV and visible-light-mediated conditions. The straightforward catalyst preparation, excellent overall yields, ease of purification, and broad substrate scope render this a highly versatile method for bioconjugation.

A new synthetic approach to thiolactones that employs an efficient acyl thiol–ene (ATE) or acyl thiol–yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.

We present direct investigations of the conformational preferences of sugars with a positively charged substituent at their anomeric centre, C-1, which display in solution, a preference for an equatorial conformation - an apparent reversal of the normal anomeric effect. The investigations focus on the protonated monosaccharide, d-xylopyranosyl imidazolium in its α and β forms, first probed in a range of different solvents through NMR measurements and then in the gas phase, free of solvent or counterion interactions, through infrared multiphoton dissociation spectroscopy. The results, when compared and discussed in the light of density functional theory, ab initio and natural bond orbital calculations, expose the possible origins of the reversed conformational preference and provide a better understanding of the factors controlling conformational choice. This journal is © The Royal Society of Chemistry 2012.

Carbon-based nanomaterials have attracted much interest during the last decade for biomedical applications. Multimodal imaging probes based on carbon nano-onions (CNOs) have emerged as a platform for bioimaging because of their cell-penetration properties and minimal systemic toxicity. Here, we describe the covalent functionalization of CNOs with fluorescein and folic acid moieties for both imaging and targeting cancer cells. The modified CNOs display high brightness and photostability in aqueous solutions and their selective and rapid uptake in two different cancer cell lines without significant cytotoxicity was demonstrated. The localization of the functionalized CNOs in late-endosomes cell compartments was revealed by a correlative approach with confocal and transmission electron microscopy. Understanding the biological response of functionalized CNOs with the capability to target cancer cells and localize the nanoparticles in the cellular environment, will pave the way for the development of a new generation of imaging probes for future biomedical studies.

A review that provides an update on an earlier review on the synthesis of glycoproteins is presented. The review focuses on highlighting key developments in the area from 2002 and provide essential information about the process. It includes specific areas of potential applications of the synthesis process to provide a detailed update. It reveals that carbohydrates continue to play a key role in the synthesis of glycoproteins. Carbohydrates are increasingly being used in synthesizing such proteins, as they are able to modify their other physiochemical properties. The review also reveals that significant developments in glycopeptide or glycoprotein synthesis are increasing the number of potential applications for such proteins. A number of biomedical researchers are developing new drug products, adopting the process of synthesizing glycoproteins.

Boron derivatives are becoming key reagents in radical chemistry. Here, we describe reactions where an organoboron derivative is used as a radical initiator, a chain-transfer reagent, and a radical precursor. For instance,B-alkylcatecholboranes, easily prepared by hydroboration of alkenes, represent a very efficient source of primary, secondary, and tertiary alkyl radicals. Their very high sensitivity toward oxygen- and heteroatom-centered radicals makes them particularly attractive for the development of radical chain processes such as conjugate addition, allylation, alkenylation, and alkynylation. Boron derivatives have also been used to develop an attractive new procedure for the reduction of radicals with alcohols and water. The selected examples presented here demonstrate that boron-containing reagents can efficiently replace tin derivatives in a wide range of radical reactions.

The effect of glycan adlayers on the electrochemical response of glassy carbon electrodes was studied using standard redox probes and complex aqueous matrices. Aryldiazonium cations of aryl-lactoside precursors were used to modify glassy carbon via spontaneous and electrochemically assisted covalent grafting. Contact angle and fluorescence binding using Peanut Agglutinin (PNA) as a diagnostic lectin indicate that electrografting results in adlayers with greater glycan surface density than those obtained via spontaneous reaction. X-ray photoelectron spectroscopy with a fluorinated analog confirmed that electrografting results in multilayers of cross-linked aryl-lactosides. Adsorption studies with Bovine Serum Albumin (BSA) show that aryl-lactoside adlayers minimize unspecific protein adsorption. However, no significant differences were detected between spontaneous and electrografted layers in their ability to resist protein fouling despite their differences in coverage. Voltammetry studies show that spontaneous grafting has minimal effects on the response of standard redox probes in solution, whereas electrografting results in additional charge transfer impedance arising from increased electrode passivation. Bare and lactoside-modified carbon electrodes were tested for the detection of caffeine before and after prolonged exposure to coffee solutions. Spontaneous grafting was found to result in optimal properties by imparting antifouling performance in these complex matrices while preserving fast interfacial charge transfer.