On the Possible Effect of Phytic Acid (Myo-Inositol Hexaphosphoric Acid, IP6) on Cytochromes P450 and Systems of Xenobiotic Metabolism in Different Hepatic Models.

As compounds of natural origin enter human body, it is necessary to investigate their possible interactions with the metabolism of drugs and xenobiotics in general, namely with the cytochrome P450 (CYP) system. Phytic acid (myo-inositol hexaphosphoric acid, IP6) is mainly present in plants but is also an endogenous compound present in mammalian cells and tissues. It has been shown to exhibit protective effect in many pathological conditions. For this paper, its interaction with CYPs was studied using human liver microsomes, primary human hepatocytes, the HepG2 cell line, and molecular docking. Docking experiments and absorption spectra demonstrated the weak ability of IP6 to interact in the heme active site of CYP1A. Molecular docking suggested that IP6 preferentially binds to the protein surface, whereas binding to the active site of CYP1A2 was found to be less probable. Subsequently, we investigated the ability of IP6 to modulate the metabolism of xenobiotics for both the mRNA expression and enzymatic activity of CYP1A enzymes. Our findings revealed that IP6 can slightly modulate the mRNA levels and enzyme activity of CYP1A. However, thanks to the relatively weak interactions of IP6 with CYPs, the chances of the mechanisms of clinically important drug-drug interactions involving IP6 are low.

Mechanistic insights into interactions between ionizable lipid nanodroplets and biomembranes.

Delivery of RNA into cells using lipid nanoparticles (LNPs) has been a significant breakthrough in RNA-based medicine, with clinical applicability expanded through the use of ionizable lipids (ILs). These unique lipids can alter their charge state in response to pH changes, which is crucial for pH-triggered endosomal escape and effective lipid-mediated RNA delivery. In this study, we conducted a comprehensive set of molecular dynamics (MD) simulations to investigate interactions between IL-containing lipid nanodroplets (LNDs) and cell membrane models. Using an atomistic resolution model, we investigated the merging process of LNDs with cell membrane models under neutral conditions relevant to an intercellular environment and acidic pH conditions found in late endosomes. Our observations revealed that at neutral pH, LNDs merged with lipid membranes while preserving the bilayer structure. Under acidic conditions, the LNDs remained attached to the bilayer without fusing into the membranes. Importantly, the presence of ILs did not disrupt the original biomembrane structure during the simulation period. The MD simulations provided valuable atomistic insights into the mechanism of interaction between IL-containing nanodroplets and biomembranes, which could aid the rational design of ILs to develop more efficient LNPs for RNA therapies.Communicated by Ramaswamy H. Sarma.

Atomistic Insights into Organization of RNA-Loaded Lipid Nanoparticles.

RNA-based therapies have shown promise in a wide range of applications, from cancer therapy, treatment of inherited diseases to vaccination. Encapsulation of RNA into ionizable lipid (IL) containing lipid nanoparticles (LNPs) has enabled its safe and targeted delivery. We present here the simulations of the self-assembly process of pH-sensitive RNA-carrying LNPs and their internal morphology. At low pH, the simulations confirm a lipid core encapsulating RNA in the hexagonal phase. Our all-atom and coarse-grained simulations show that an RNA molecule inside an LNP is protected from interactions with ions by being enveloped in the charged ILs. At neutral pH, representing the environment after LNP administration into human tissues, LNPs expelled most of the encapsulated RNA and water and formed separate bulk IL-rich and ordered the helper-lipid-rich phase. Helper lipids arranged themselves to be in contact with RNA or water. The presented models provide atomistic understanding of the LNP structure and open a way to investigate them in silico, varying the LNP composition or interacting with other biostructures aiming at increasing the efficiency of RNA-based medicine.

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds.

Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold naïve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQIVYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK- or Cys322-targeting drugs have a reduced potency to cause aggregation of naïve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK- or Cys322-targeting drugs may act as prophylactic agents against tau seeding.

Role of Ionizable Lipids in SARS-CoV-2 Vaccines As Revealed by Molecular Dynamics Simulations: From Membrane Structure to Interaction with mRNA Fragments.

Recent advances in RNA-based medicine have provided new opportunities for the global current challenge, i.e., the COVID-19 pandemic. Novel vaccines are based on a messenger RNA (mRNA) motif with a lipid nanoparticle (LNP) vector, consisting of high content of unique pH-sensitive ionizable lipids (ILs). Here we provide molecular insights into the role of the ILs and lipid mixtures used in current mRNA vaccines. We observed that the lipid mixtures adopted a nonlamellar organization, with ILs separating into a very disordered, pH-sensitive phase. We describe structural differences of the two ILs leading to their different congregation, with implications for the vaccine stability. Finally, as RNA interacts preferentially with IL-rich phases located at the regions with high curvature of lipid phase, local changes in RNA flexibility and base pairing are induced by lipids. A proper atomistic understanding of RNA-lipid interactions may enable rational tailoring of LNP composition for efficient RNA delivery.

MolMeDB: Molecules on Membranes Database.

Biological membranes act as barriers or reservoirs for many compounds within the human body. As such, they play an important role in pharmacokinetics and pharmacodynamics of drugs and other molecular species. Until now, most membrane/drug interactions have been inferred from simple partitioning between octanol and water phases. However, the observed variability in membrane composition and among compounds themselves stretches beyond such simplification as there are multiple drug-membrane interactions. Numerous experimental and theoretical approaches are used to determine the molecule-membrane interactions with variable accuracy, but there is no open resource for their critical comparison. For this reason, we have built Molecules on Membranes Database (MolMeDB), which gathers data about over 3600 compound-membrane interactions including partitioning, penetration and positioning. The data have been collected from scientific articles published in peer-reviewed journals and complemented by in-house calculations from high-throughput COSMOmic approach to set up a baseline for further comparison. The data in MolMeDB are fully searchable and browsable by means of name, SMILES, membrane, method or dataset and we offer the collected data openly for further reuse and we are open to further additions. MolMeDB can be a powerful tool that could help researchers better understand the role of membranes and to compare individual approaches used for the study of molecule/membrane interactions.

Membrane-attached mammalian cytochromes P450: An overview of the membrane's effects on structure, drug binding, and interactions with redox partners.

Mammalian cytochromes P450 are an important class of enzymes involved in the biotransformation of many endo- and exogenous compounds. Cytochrome P450 isoforms are attached to the membrane of the endoplasmic reticulum or mitochondria, and their catalytic domains move along the membrane surface while being partially immersed in the membrane environment. Their active sites are connected to both the membrane and cytosolic environments via a complex network of access channels. Consequently, they can accept substrates from both environments. The membrane also supports the interactions of cytochromes P450 with their redox partners. In this review, we provide an overview of current knowledge of the structure, flexibility, and interactions with substrates and redox partners of cytochrome P450 on membranes, amalgamating information derived from both experiments and simulations.