Nanostructural Modulation of G-Quadruplex DNA in Neurodegeneration: Orotate Interaction Revealed Through Experimental and Computational Approaches.

The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G-quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (GC) repeats in nuclear DNA sequences.

Structural commonalities determined by physicochemical principles in the complex polymorphism of the amyloid state of proteins.

Advances in solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryoEM) have revealed the polymorphic nature of the amyloid state of proteins. Given the association of amyloid with protein misfolding disorders, it is important to understand the principles underlying this polymorphism. To address this problem, we combined computational tools to predict the specific regions of the sequence forming the β-spine of amyloid fibrils with the availability of 30, 83 and 24 amyloid structures deposited in the Protein Data Bank (PDB) and Amyloid Atlas (AAt) for the amyloid β (Aβ) peptide, α-synuclein (αS), and the 4R isoforms of tau, associated with Alzheimer's disease, Parkinson's disease, and various tauopathies, respectively.

Mild-Temperature Catalyzed Hydrosilylation for Simplified Carbohydrate Functionalization of Porous Silicon Nanoparticles.

Porous silicon is one of the most explored nanostructured materials in various biomedical applications owing to its remarkable properties. However, its inherent chemical instability mandates a robust surface modification procedure, and proper surface bioengineering is essential to ensure its effectiveness in the biomedical field. In this study, we introduce a one-pot functionalization strategy that simultaneously stabilizes porous silicon nanoparticles and decorates their surface with carbohydrates through hydrosilylation chemistry, combining mild temperatures and a Lewis acid catalyst.

A CD Study of a Structure-Based Selection of -Heterocyclic Bis-Carbene Gold(I) Complexes as Potential Ligands of the G-Quadruplex-Forming Human Telomeric hTel23 Sequence.

Herein, we report the structure-based selection via molecular docking of four -heterocyclic bis-carbene gold(I) complexes, whose potential as ligands for the hTel23 G-quadruplex structure has been investigated using circular dichroism (CD) spectroscopy, CD melting, and polyacrylamide gel electrophoresis (PAGE). The complex containing a bis(1,2,3,4,6,7,8,9-octahydro-11-11-pyridazino[1,2-a]indazol-11-yl) scaffold induces a transition from the hybrid (3 + 1) topology to a prevalent parallel G-quadruplex conformation, whereas the complex featuring a bis(2-(2-acetamidoethyl)-3-imidazo[1,5-a]pyridin-3(2)-yl) moiety disrupted the original G-quadruplex structure. These results deserve particular attention in light of the recent findings on the pathological involvements of G-quadruplexes in neurodegenerative diseases.