Paper-based electrochemical device for early detection of integrin αvβ6 expressing tumors.

Despite progress in the prevention and diagnosis of cancer, current technologies for tumor detection present several limitations including invasiveness, toxicity, inaccuracy, lengthy testing duration and high cost. Therefore, innovative diagnostic techniques that integrate knowledge from biology, oncology, medicinal and analytical chemistry are now quickly emerging in the attempt to address these issues. Following this approach, here we developed a paper-based electrochemical device for detecting cancer-derived Small Extracellular Vesicles (S-EVs) in fluids.

Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.

Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 (), the only known peptide acting through this mechanism.

A combined approach of structure-based virtual screening and NMR to interrupt the PD-1/PD-L1 axis: Biphenyl-benzimidazole containing compounds as novel PD-L1 inhibitors.

Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest.

Molecular View on the RGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles.

Receptor-selective peptides are widely used as smart carriers for specific tumor-targeted delivery. A remarkable example is the cyclic nonapeptide RGD (CRGDKPGDC, ) that couples intrinsic cytotoxic effects with striking tumor-homing properties. These peculiar features are based on a rather complex multistep mechanism of action, where the primary event is the recognition of RGD integrins.

Isocyanides as Catalytic Electron Acceptors in the Visible Light Promoted Oxidative Formation of Benzyl and Acyl Radicals.

The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provide key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts.

Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design.

Today it is widely recognized that the PD-1/PD-L1 axis plays a fundamental role in escaping the immune system in cancers, so that anti-PD-1/PD-L1 antibodies have been evaluated for their antitumor properties in more than 1000 clinical trials. As a result, some of them have entered the market revolutionizing the treatment landscape of specific cancer types. Nonetheless, a new era based on the development of small molecules as anti PD-L1 drugs has begun.

Bacterial lipids drive compartmentalization on the nanoscale.

The design of cellular functions in synthetic systems, inspired by the internal partitioning of living cells, is a constantly growing research field that is paving the way to a large number of new remarkable applications. Several hierarchies of internal compartments like polymersomes, liposomes, and membranes are used to control the transport, release, and chemistry of encapsulated species. However, the experimental characterization and the comprehension of glycolipid mesostructures are far from being fully addressed.

HuR modulation counteracts lipopolysaccharide response in murine macrophages.

Lipopolysaccharide (LPS) exposure to macrophages induces an inflammatory response, which is regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) is an RNA-binding protein that regulates cytokines and chemokines transcripts containing AU/U-rich elements (AREs) and mediates the LPS-induced response. Here, we show that small-molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages.

Direct or Indirect ESPT Mechanism in CFP psamFP488? A Theoretical-Computational Investigation.

Fluorescent Proteins are widely studied for their multiple applications in technological and biotechnological fields. Despite this, they continue to represent a challenge in terms of a complete understanding of all the non-equilibrium photo-induced processes that rule their properties. In this context, a theoretical-computational approach can support experimental results in unveiling and understanding the processes taking place after electronic excitation.

Enriching the Arsenal of Pharmacological Tools against MICAL2.

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells.

Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors.

The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 () as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence.

Efficient Hybrid Particle-Field Coarse-Grained Model of Polymer Filler Interactions: Multiscale Hierarchical Structure of Carbon Black Particles in Contact with Polyethylene.

In the present study, we propose, validate, and give first applications for large-scale systems of coarse-grained models suitable for filler/polymer interfaces based on carbon black (CB) and polyethylene (PE). The computational efficiency of the proposed approach, based on hybrid particle-field models (hPF), allows large-scale simulations of CB primary particles of realistic size (∼20 nm) embedded in PE melts. The molecular detailed models, here introduced, allow a microscopic description of the bound layer, through the analysis of the conformational behavior of PE chains adsorbed on different surface sites of CB primary particles, where the conformational behavior of adsorbed chains is different from models based on flat infinite surfaces.

A Not Obvious Correlation Between the Structure of Green Fluorescent Protein Chromophore Pocket and Hydrogen Bond Dynamics: A Choreography From Molecular Dynamics.

The Green Fluorescent Protein (GFP) is a widely studied chemical system both for its large amount of applications and the complexity of the excited state proton transfer responsible of the change in the protonation state of the chromophore. A detailed investigation on the structure of the chromophore environment and the influence of chromophore form (either neutral or anionic) on it is of crucial importance to understand how these factors could potentially influence the protein function. In this study, we perform a detailed computational investigation based on the analysis of molecular dynamics simulations, to disentangle the main structural quantities determining the fine balance in the chromophore environment.

Multiresolution continuous wavelet transform for studying coupled solute-solvent vibrations molecular dynamics.

Vibrational analysis in solution and the theoretical determination of infrared and Raman spectra are of key importance in many fields of chemical interest. Vibrational band dynamics of molecules and their sensitivity to the environment can also be captured by these spectroscopies in their time dependent version. However, it is often difficult to provide an interpretation of the experimental data at the molecular scale, such as molecular mechanisms or the processes hidden behind them.

Time-Resolved Vibrational Analysis of Excited State Ab Initio Molecular Dynamics to Understand Photorelaxation: The Case of the Pyranine Photoacid in Aqueous Solution.

We present a novel time-resolved vibrational analysis for studying photoinduced nuclear relaxation. Generalized modes velocities are defined from ab initio molecular dynamics and wavelet transformed, providing the time localization of vibrational signals in the electronic excited state. The photoexcited pyranine in aqueous solution is presented as a case study.

Ab-initio molecular dynamics and hybrid explicit-implicit solvation model for aqueous and nonaqueous solvents: GFP chromophore in water and methanol solution as case study.

Solute-solvent interactions are proxies for understanding how the electronic density of a chromophore interacts with the environment in a more exhaustive way. The subtle balance between polarization, electrostatic, and non-bonded interactions need to be accurately described to obtain good agreement between simulations and experiments. First principles approaches providing accurate configurational sampling through molecular dynamics may be a suitable choice to describe solvent effects on solute chemical-physical properties and spectroscopic features, such as optical absorption of dyes.

Simulation of self-heating process on the nanoscale: a multiscale approach for molecular models of nanocomposite materials.

A theoretical-computational protocol to model the Joule heating process in nanocomposite materials is presented. The proposed modeling strategy is based on post processing of trajectories obtained from large scale molecular simulations. This protocol, based on molecular models, is the first one to be applied to organic nanocomposites based on carbon nanotubes (CNT).

Nonequilibrium Environment Dynamics in a Frequency-Dependent Polarizable Embedding Model.

Hybrid quantum mechanical/molecular mechanical (QM/MM) models are some of the most powerful and computationally feasible approaches to account for solvent effects or more general environmental perturbations on quantum chemical systems. In their more recent formulations (known as polarizable embedding) they can account for electrostatic and mutual polarization effects between the QM and the MM subsystems. In this paper, a polarizable embedding scheme based on induced dipoles that is able both to describe electron evolution of the embedded QM system in an efficient manner as well as to capture the frequency dependent behavior of the solvent is proposed, namely, ωMMPol.

The mechanism of a green fluorescent protein proton shuttle unveiled in the time-resolved frequency domain by excited state dynamics.

We simulated an excited state proton transfer in green fluorescent protein by excited state dynamics, and examined the reaction mechanism in both the time and the frequency domain through a multi resolution wavelet analysis. This original approach allowed us, for the first time, to directly compare the trends of photoactivated vibrations to femtosecond stimulated Raman spectroscopy results, and to give an unequivocal interpretation of the role played by low frequency modes in promoting the reaction. We could attribute the main driving force of the reaction to an important photoinduced softening of the ring-ring orientational motion of the chromophore, thus permitting the tightening of the hydrogen bond network and the opening of the reaction pathway.

Turn-on fluorescence detection of protein by molecularly imprinted hydrogels based on supramolecular assembly of peptide multi-functional blocks.

Synthetic receptors for biomacromolecules lack the supramolecular self-assembly behavior typical of biological systems. Here we propose a new method for the preparation of protein imprinted polymers based on the specific interaction of a peptide multi-functional block with a protein target. This peptide block contains a protein-binding peptide domain, a polymerizable moiety at the C-terminus and an environment-sensitive fluorescent molecule at the N-terminus.

Coupling Real-Time Time-Dependent Density Functional Theory with Polarizable Force Field.

Real-time time-dependent density functional theory (RT-TDDFT) is a powerful tool for obtaining spectroscopic observables and understanding complex, time-dependent properties. Currently, performing RT-TDDFT calculations on large, fully quantum mechanical systems is not computationally feasible. Previously, polarizable mixed quantum mechanical and molecular mechanical (QM/MMPol) models have been successful in providing accurate, yet efficient, approximations to a fully quantum mechanical system.