Photoresponsive Control of G-Quadruplex DNA Systems

[Image: see text] G-quadruplex (G4) oligonucleotide secondary structures have recently attracted significant attention as therapeutic targets owing to their occurrence in human oncogene promoter sequences and the genome of pathogenic organisms. G4s also demonstrate interesting catalytic activities in their own right, as well as the ability to act as scaffolds for the development of DNA-based materials and nanodevices. Owing to this diverse range of opportunities to exploit G4 in a variety of applications, several strategies to control G4 structure and function have emerged. Interrogating the role of G4s in biology requires the delivery of small-molecule ligands that promote its formation under physiological conditions, while exploiting G4 in the development of responsive nanodevices is normally achieved by the addition and sequestration of the metal ions required for the stabilization of the folded structure. Although these strategies prove successful, neither allows the system in question to be controlled externally. Meanwhile, light has proven to be an attractive means for the control of DNA-based systems as it is noninvasive, can be delivered with high spatiotemporal precision, and is orthogonal to many chemical and biological processes. A plethora of photoresponsive DNA systems have been reported to date; however, the vast majority deploy photoreactive moieties to control the stability and assembly of duplex DNA hybrids. Despite the unique opportunities afforded by the regulation of G-quadruplex formation in biology, catalysis, and nanotechnology, comparatively little attention has been devoted to the design of photoresponsive G4-based systems. In this Perspective, we consider the potential of photoresponsive G4 assemblies and examine the strategies that may be used to engineer these systems toward a variety of applications. Through an overview of the main developments in the field to date, we highlight recent progress made toward this exciting goal and the emerging opportunities that remain ripe for further exploration in the coming years

Carbon Dots as an Emergent Class of Antimicrobial Agents

Antimicrobial resistance is a recognized global challenge. Tools for bacterial detection can combat antimicrobial resistance by facilitating evidence-based antibiotic prescribing, thus avoiding their overprescription, which contributes to the spread of resistance. Unfortunately, traditional culture-based identification methods take at least a day, while emerging alternatives are limited by high cost and a requirement for skilled operators. Moreover, photodynamic inactivation of bacteria promoted by photosensitisers could be considered as one of the most promising strategies in the fight against multidrug resistance pathogens. In this context, carbon dots (CDs) have been identified as a promising class of photosensitiser nanomaterials for the specific detection and inactivation of different bacterial species. CDs possess exceptional and tuneable chemical and photoelectric properties that make them excellent candidates for antibacterial theranostic applications, such as great chemical stability, high water solubility, low toxicity and excellent biocompatibility. In this review, we will summarize the most recent advances on the use of CDs as antimicrobial agents, including the most commonly used methodologies for CD and CD/composites syntheses and their antibacterial properties in both in vitro and in vivo models developed in the last 3 years.Peer reviewe

Cyclooctyne [60]fullerene hexakis adducts: a globular scaffold for copper-free click chemistry

The synthesis of a new highly symmetric hexakis adduct of C60 appended with 12 cyclooctyne moieties has been carried out. This compound has been used for the copper-free strain-promoted cycloaddition reaction to a series of azides with excellent yields. This strategy for the obtention of clicked adducts of [60]fullerene is of special interest for biological applicationsEuropean Research Council ERC-320441-Chir all carbonMinisterio de Economía y Competitividad CTQ2014-52045-R, CTQ2014-52328-PComunidad Autónoma de Madrid S2013/MIT-28

A Peptide/Fullerene Hybrid for Multivalent Recognition of E-Selectin

Molecular recognition through ligand-receptor interactions is a very important mechanism for metastatic processes. Among all of them, multivalent protein-carbohydrate interactions play a fundamental role in tumor cell-endothelial cell recognition processes. In particular, the interaction between SLex and SLea expressed in circulating tumor cells and proteins of the family of selectins, overexpressed in endothelial cells. Unlike tumor cells, vascular endothelial cells receptors are a stable target not subjected to genetic modifications. In addition, the elimination of a single endothelial cell involves the death of hundreds of tumor cells. Targeting endothelial receptors cells offers a high potential in tumor diagnosis and therapy. SLex and SLea are the natural ligands of selectins, but their complicated chemical synthesis and their low affinity for selectins made difficult to continue with their development. Recently, through "phase display" it was identified a simple peptide with a linear sequence of seven amino acids (Ile-Glu-Leu-Leu-Gln-Ala-Arg) called IELLQAR that interacts specifically with selectins. IELLQAR is a very simple compound, which can be synthesized using SPPS. IELLQAR can be functionalized and easily conjugated to fullerenes for its multivalent presentation. In addition, it can be combined with diagnostic and therapeutic agents. References [1] Smith, B. A. H.; Bertozzi, C. Nat. Rev. Drug Discov. 2021, 20, 217.243. [2] Fukuda, M. N. et al. Cancer Res. 2000, 60, 450-456 [3] (a) Ramos-Soriano, J. et al. Chem. Commun. 2016, 52, 10544-10546; (b) Ramos-Soriano, J. et al. J. Org. Chem. 2018, 83, 1727-1736.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Cyclooctyne [60]fullerene hexakis adducts: a globular scaffold for copper-free click chemistry

The synthesis of a new highly symmetric hexakis adduct of C60 appended with 12 cyclooctyne moieties has been carried out. This compound has been used for the copper-free strain-promoted cycloaddition reaction to a series of azides with excellent yields.This strategy for the obtention of clicked adducts of [60]fullerene is of special interest for biological applications

A CFD Modelling Approach for the Operation Analysis of an Exhaust Backpressure Valve Used in a Euro 6 Diesel Engine.

Harvesting residual thermal energy from exhaust gases with thermoelectric generators is one of the paths that are currently being explored to achieve more sustainable and environmentally friendly means of transport. In some cases, thermoelectric generators are installed in a by-pass configuration to regulate the mass flow entering the thermoelectric generator. Some manufacturers are using throttle valves with electromechanical actuators and electronic control in the exhaust pipe to improve techniques for active control of pollutant emissions in reciprocating internal combustion engines, such as the exhaust gas recirculation. The above-mentioned circumstances have motivated the approach of this work: computational fluid dynamics (CFD) modelling of the operation of a throttle valve used for establishing adequate exhaust backpressure conditions to achieve the low pressure exhaust gas recirculation in Euro 6 engines. The aim of this model is to understand the flow control process with these types of valves in order to incorporate them in an exhaust system that will include two thermoelectric generators used to convert residual thermal energy into electrical energy. This work presents a computational model of the flow through the throttle valve under different temperatures and mass flow rates of the exhaust gas with different closing positions. For all cases, the values of the pressure drop were obtained. In all cases studied, the level of agreement between the modelled and experimental results exceeds 90%. The developed model has helped to propose a correlation to estimate the mass flow rate of exhaust gas from easily measurable quantitiesPartial funding for open access charge: Universidad de Málag

Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology

We report the selective targeting of telomeric G4 DNA with a dithienylethene ligand and demonstrate the robust visible-light mediated switching of the G4 ligand binding mode and G-tetrad structure in physiologically-relevant conditions. The toxicity of the ligand to cervical cancer cells is modulated by the photoisomeric state of the ligand, indicating for the first time the potential of G4 to serve as a target for photopharmacological strategies.MPO thanks the Bristol Chemical Synthesis Centre forDoctoral Training, funded by EPSRC (EP/L015366/1) and theUniversity of Bristol, for a PhD studentship, JRS acknowledges aMSCA fellowship (project 843720-BioNanoProbes). SH and AJMthanks EPSRC for support (grant numbers EP/M015378/1 andEP/M022609/1). This work was carried out using the computationalfacilities of the Advanced Computing Research Centre, University ofBristol – http://www.bris.ac.uk/acrc/ SS thanks the Bristol Centre ForFunctional Nanomaterials (EPSRC EP/L016648/1). JCMS thanks theSpanish Ministerio de Economı ́a y Competitividad (Grant CTQ2015-64275-P and RTI2018-099036-B-I00). MCG thanks the EuropeanResearch Council (ERC-COG: 64823

Carbon dot-based fluorescent antibody nanoprobes as brain tumour glioblastoma diagnostics

The development of efficient and sensitive tools for the detection of brain cancer in patients is of the utmost importance particularly because many of these tumours go undiagnosed until the disease has advanced and when treatment is less effective. Current strategies employ antibodies (Abs) to detect Glial Fibrillary Acid Protein (GFAP) in tissue samples, since GFAP is unique to the brain and not present in normal peripheral blood, and it relies on fluorescent reporters. Herein we describe a low cost, practical and general method for the labelling of proteins and antibodies with fluorescent carbon dots (CD) to generate diagnostic probes that are robust, photostable and applicable to the clinical setting. The two-step protocol relies on the conjugation of a dibenzocyclooctyne (DBCO)-functionalised CD with azide functionalised proteins by combining amide conjugation and strain promoted alkyne–azide cycloaddition (SPAAC) ligation chemistry. The new class of Ab-CD conjugates developed using this strategy was successfully used for the immunohistochemical staining of human brain tissues of patients with glioblastoma (GBM) validating the approach. Overall, these novel fluorescent probes offer a promising and versatile strategy in terms of costs, photostability and applicability which can be extended to other Abs and protein systems

Influence of the reducing-end anomeric configuration of the Man9 epitope on DC-SIGN recognition

High-mannose (Man9GlcNAc2) is the main carbohydrate unit present in viral envelope glycoproteins such as gp120 of HIV and the GP1 of Ebola virus. This oligosaccharide comprises the Man9 epitope conjugated to two terminal N-acetylglucosamines by otherwise rarely-encountered β-mannose glycosidic bond. Formation of this challenging linkage is the bottleneck of the few synthetic approaches described to prepare high mannose. Herein, we report the synthesis of the Man9 epitope with both alpha and beta configurations at the reducing end, and subsequent evaluation of the impact of this configuration on binding to natural receptor of high-mannose, DC-SIGN. Using fluorescence polarization assays, we demonstrate that both anomers bind to DC-SIGN with comparable affinity. These relevant results therefore indicate that the more synthetically-accesible Man9 alpha epitope may be deployed as ligand for DC-SIGN in both in vitro and in vivo biological assays.Ministerio de Economía y Competitividad CTQ2017- 86265-P, PGC2018-099497-B-100, IJCI-2015-2327