Mass Spectrometry Analysis of Chemically and Collisionally Dissociated Molecular Glue- and PROTAC-Mediated Protein Complexes Informs on Disassembly Pathways.

Molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs) are used to modulate protein-protein interactions (PPIs), via induced proximity between compounds that have little or no affinity for each other naturally. They promote either reversible inhibition or selective degradation of a target protein, including ones deemed undruggable by traditional therapeutics. Though native MS (nMS) is capable of analyzing multiprotein complexes, the behavior of these artificially induced compounds in the gas phase is still not fully understood, and the number of publications over the past few years is still rather limited.

Global Aromatic Ring Currents in Neutral Porphyrin Nanobelts.

The ability of a ring-shaped molecule to sustain a global aromatic or antiaromatic ring current when placed in a magnetic field indicates that its electronic wave function is coherently delocalized around its whole circumference. Large molecules that display this behavior are attractive components for molecular electronic devices, but this phenomenon is rare in neutral molecules with circuits of more than 40 π-electrons. Here, we use theoretical methods to investigate how the global ring currents evolve with increasing ring size in cyclic molecular nanobelts built from edge-fused porphyrins.

The synthesis and structural aspects of the perbromo-functionalised thiaboranes -SBBr ( = 5, 9, 11): the solid-state structure of the octahedral -SBBr, governed by strong dihalogen contacts.

Co-pyrolysis reactions of BBr with SBr at 350 °C yielded the brominated thiaboranes -SBBr (1), -1-SBBr (2) and -SBBr (3), confirmed by high-resolution mass spectrometry, experimental and computational B NMR spectroscopy. The strong Br(σ-hole)⋯Br(ring) attraction has been the decisive energy contribution in the crystal of 1.

Ion pairing in aqueous tetramethylammonium-acetate solutions by neutron scattering and molecular dynamics simulations.

Tetramethylammonium (TMA) is a ubiquitous cationic motif in biochemistry, found in the charged choline headgroup of membrane phospholipids and in tri-methylated lysine residues, which modulates histone-DNA interactions and impacts epigenetic mechanisms. TMA interactions with anionic species, particularly carboxylate groups of amino acid residues and extracellular sugars, are of substantial biological relevance, as these interactions mediate a wide range of cellular processes. This study investigates the molecular interactions between TMA and acetate, representing carboxylate-containing groups, using neutron scattering experiments complemented by force fields and molecular dynamics (MD) simulations.

Chiroptical spectroscopy complemented by quantum chemical calculations accurately predicts the absolute configuration of P-chirogenic compounds.

Model P-chirogenic phosphonates derived from isopinocampheol, offering an excellent experimental system for studying chirality on the phosphorus chiral center, were studied using a set of chiroptical methods including ECD, VCD and ROA. Thanks to their rigidity, limiting the number of possible conformers, we successfully correlated the experimental UV-vis/ECD, IR/VCD and Raman/ROA results with DFT calculations. This allowed us to confidently assign the absolute configuration of our models, and our assignment is consistent with X-ray diffraction (XRD) data.

Evaluation of the role of unconventional prefoldin RPB5 interactor (URI1) in hepatitis B virus infection.

Hepatitis B virus (HBV) infection can cause liver disease and lead to hepatocellular carcinoma (HCC). To better understand the factors involved in viral infection and pathogenesis and to develop novel therapies, it is crucial to investigate virus-host interactions. HBV infection has been shown to increase the expression of the unconventional prefoldin RPB5 interactor (URI1), a cellular protein that promotes liver tumorigenesis and HCC metastasis.

Solid Lipid Nanoparticles Coated with Glucosylated poly(2-oxazoline)s: A Supramolecular Toolbox Approach.

Multifunctional polymers are interesting substances for the formulation of drug molecules that cannot be administered in their pure form due to their pharmacokinetic profiles or side effects. Polymer-drug formulations can enhance pharmacological properties or create tissue specificity by encapsulating the drug into nanocontainers, or stabilizing nanoparticles for drug transport. We present the synthesis of multifunctional poly(2-ethyl-2-oxazoline--2-glyco-2-oxazoline)s containing two reactive end groups, and an additional hydrophobic anchor at one end of the molecule.

Breaking the cellular defense: the role of autophagy evasion in virulence.

Many pathogens have evolved sophisticated strategies to evade autophagy, a crucial cellular defense mechanism that typically targets and degrades invading microorganisms. By subverting or inhibiting autophagy, these pathogens can create a more favorable environment for their replication and survival within the host. For instance, some bacteria secrete factors that block autophagosome formation, while others might escape from autophagosomes before degradation.

LEGO-Lipophosphonoxin membrane activity is enhanced by presence of phosphatidylethanolamine but hindered by outer membrane.

Finding effective antibiotics against multi-resistant strains of bacteria has been a challenging race. Linker-Evolved-Group-Optimized-Lipophosphonoxins (LEGO-LPPOs) are small modular synthetic antibacterial compounds targeting the cytoplasmic membrane. Here we focused on understanding the reasons for the variable efficacy of selected LEGO-LPPOs (LEGO-1, LEGO-2, LEGO-3, and LEGO-4) differing in hydrophobic and linker module structure and length.

Solid-State Photoswitching of Hydrazones Based on Excited-State Intramolecular Proton Transfer.

The development of new photochromic systems is motivated by the possibility of controlling the properties and functions of materials with high spatial and temporal resolution in a reversible manner. While there are several classes of photoswitches operating in solution, the design of systems efficiently operating in the solid state remains highly challenging, mainly due to limitations related to confinement effects. Triaryl-hydrazones represent a relatively new subclass of bistable hydrazone photoswitches exhibiting efficient / photochromism in solution.

Assessment of L. and Lipophosphonoxin (DR-6180) Combination for Wound Repair: Bridging the Gap Between Phytomedicine and Organic Chemistry.

L. (AE) has a rich tradition of use in wound healing improvement across various cultures worldwide. In previous studies, we revealed that L.

TIM3 in COVID-19; A potential hallmark?

Coronavirus disease 2019 (COVID-19) is a highly contagious viral disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It can manifest as mild to severe flu-like and non-flu-like symptoms and signs, which are associated with immune dysfunction and increased mortality. The findings from COVID-19 patients imply a link between immune system abnormalities such as impaired T-cell responses or cytokine imbalances and increased risk for worse clinical outcomes, which has not been fully understood.

Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells.

The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets.

End-Point Affinity Estimation of Galectin Ligands by Classical and Semiempirical Quantum Mechanical Potentials.

The use of quantum mechanical potentials in protein-ligand affinity prediction is becoming increasingly feasible with growing computational power. To move forward, validation of such potentials on real-world challenges is necessary. To this end, we have collated an extensive set of over a thousand galectin inhibitors with known affinities and docked them into galectin-3.

PM6-ML: The Synergy of Semiempirical Quantum Chemistry and Machine Learning Transformed into a Practical Computational Method.

Machine learning (ML) methods offer a promising route to the construction of universal molecular potentials with high accuracy and low computational cost. It is becoming evident that integrating physical principles into these models, or utilizing them in a Δ-ML scheme, significantly enhances their robustness and transferability. This paper introduces PM6-ML, a Δ-ML method that synergizes the semiempirical quantum-mechanical (SQM) method PM6 with a state-of-the-art ML potential applied as a universal correction.

Cationic -Tricarbollide μ-10,11-H-10,11-H-7-MeN--7,8,9-CBH and Its Halogenated Derivatives: The Slow Iodination Process Occurring through Cationic Iodonium Tricarbollides.

A series of -tricarbollides based on 10,11-X-7-MeN--7,8,9-CBH (X = H, Cl, Br, I) and their protonated, i.e. cationic, counterparts, which have an extra H-bridge over the B10-B11 vector in the open pentagonal belt, were prepared.

On the Role of Hydrogen Migrations in the Taxadiene System.

Taxa-4,11-diene is made by the taxa-4,11-diene synthase (TxS) from Taxus brevifolia. The unique reactivity of the taxane system is characterised by long distance hydrogen migrations in the biosynthesis. This study demonstrates that selective long range hydrogen migrations also play a role in the high energy process of the EI-MS fragmentation of taxa-4,11-diene.

Enzymatic synthesis of reactive RNA probes containing squaramate-linked cytidine or adenosine for bioconjugations and cross-linking with lysine-containing peptides and proteins.

Protein-RNA interactions play important biological roles and hence reactive RNA probes for cross-linking with proteins are important tools in their identification and study. To this end, we designed and synthesized 5'-O-triphosphates bearing a reactive squaramate group attached to position 5 of cytidine or position 7 of 7-deazaadenosine and used them as substrates for polymerase synthesis of modified RNA. In vitro transcription with T7 RNA polymerase or primer extension using TGK polymerase was used for synthesis of squaramate-modified RNA probes which underwent covalent bioconjugations with amine-linked fluorophore and lysine-containing peptides and proteins including several viral RNA polymerases or HIV reverse transcriptase.

Global analysis by LC-MS/MS of N6-methyladenosine and inosine in mRNA reveal complex incidence.

The precise and unambiguous detection and quantification of internal RNA modifications represents a critical step for understanding their physiological functions. The methods of direct RNA sequencing are quickly developing allowing for the precise location of internal RNA marks. This detection is however not quantitative and still presents detection limits.

JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging.

Purpose: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity.

Optimal control: From sensitivity improvement to alternative pulse-sequence design in solid-state NMR.

Exciting developments in new experimental methods for multidimensional solid-state NMR spectroscopy have recently been achieved using optimal-control theory. These results, in turn, have triggered the development of new pulse sequences based on traditional analytical theories. This trend article summarises the key steps leading to these advancements.

Raman scattering of water in vicinity of polar complexes: Computational insight into baseline subtraction.

Water is a greatly convenient solvent in Raman spectroscopy. However, non-additive effects sometimes make its signal difficult to subtract. To understand these effects, spectra for clusters of model ions, including transition metal complexes and water molecules, were simulated and analyzed.