Phosphonodithioester–Amine Coupling as a Key Reaction Step for the Design of Cationic Amphiphiles Used for Gene Delivery

A convergent synthesis of cationic amphiphilic compounds is reported here with the use of the phosphonodithioester–amine coupling (PAC) reaction. This versatile reaction occurs at room temperature without any catalyst, allowing binding of the lipid moiety to a polar head group. This strategy is illustrated with the use of two lipid units featuring either two oleyl chains or two-branched saturated lipid chains. The final cationic amphiphiles were evaluated as carriers for plasmid DNA delivery in four cell lines (A549, Calu3, CFBE and 16HBE) and were compared to standards (BSV36 and KLN47). These new amphiphilic derivatives, which were formulated with DOPE or DOPE-cholesterol as helper lipids, feature high transfection efficacies when associated with DOPE. The highest transfection efficacies were observed in the four cell lines at low charge ratios (CR = 0.7, 1 or 2). At these CRs, no toxic effects were detected. Altogether, this new synthesis scheme using the PAC reaction opens up new possibilities for investigating the effects of lipid or polar head groups on transfection efficacies.

The exploration of Thermococcus barophilus lipidome reveals the widest variety of phosphoglycolipids in Thermococcales.

One of the most distinctive characteristics of Archaea is their unique lipids. While the general nature of archaeal lipids has been linked to their tolerance to extreme conditions, little is known about the diversity of lipidic structures Archaea are able to synthesize, which hinders the elucidation of the physicochemical properties of their cell membrane. In an effort to widen the known lipid repertoire of the piezophilic and hyperthermophilic model archaeon Thermococcus barophilus, we comprehensively characterized its intact polar lipid (IPL), core lipid (CL), and polar head group compositions using a combination of cutting-edge liquid chromatography and mass spectrometric ionization systems. We tentatively identified 82 different IPLs based on five distinct CLs and 10 polar head group derivatives of phosphatidylhexoses, including compounds reported here for the first time, e.g., di-N-acetylhexosamine phosphatidylhexose-bearing lipids. Despite having extended the knowledge on the lipidome, our results also indicate that the majority of T. barophilus lipids remain inaccessible to current analytical procedures and that improvements in lipid extraction and analysis are still required. This expanded yet incomplete lipidome nonetheless opens new avenues for understanding the physiology, physicochemical properties, and organization of the membrane in this archaeon as well as other Archaea.

Comprehensive study of α-terpineol-loaded oil-in-water (O/W) nanoemulsion: interfacial property, formulation, physical and chemical stability

In this study, the interfacial ability of α-terpineol (α-TOH) was reported, followed by its trapping into oil-in-water (O/W) nanoemulsion as active-ingredient and the long-term observation of this nanosystem influenced by the storage-time (410-days) and temperature (5, 25, 50 °C). The results indicated that the α-TOH can reduce the interfacial tension on the liquid-liquid interface (ΔG°m = −1.81 KJ mol−1; surface density = 8.19 × 10−6 mol m−2; polar head group area = 20.29 Å2), in the absence or presence of surfactant. The O/W nanoemulsion loaded with a high amount of α-TOH (90 mg mL−1; 9α-TOH-NE) into the oil phase was successfully formulated. Among the physical parameters, the mean droplet diameter (MDD) showed a great thermal dependence influenced by the storage-temperature, where the Ostwald ripening (OR) was identified as the main destabilizing phenomena that was taking place on 9α-TOH-NE at 5 and 25 °C along with time. Despite of the physical instability, the integrity of both nanoemulsion at 5 °C and 25 °C was fully preserved up to 410th day, displaying a homogeneous and comparable appearance by visual observation. On contrary, a non-thermal dependence was found for chemical stability, where over 88% of the initial amount of the α-TOH nanoemulsified remained in both 9α-TOH-NE at 5 and 25 °C, up to 410th day. Beyond the key data reported for α-TOH, the importance of this research relies on the long-term tracking of a nanostructured system which can be useful for scientific community as a model for a robust evaluation of nanoemulsion loaded with flavor oils.

Molecular basis of UHRF1 allosteric activation for synergistic histone modification binding by PI5P

Chromatin marks are recognized by distinct binding modules many of which are embedded in multidomain proteins or complexes. How the different protein functionalities of complex chromatin modulators are regulated is often unclear. Using a combination of biochemical, biophysical and structural approaches we delineated the regulation of the H3unmodified and H3K9me binding activities of the multidomain UHRF1 protein. The phosphoinositide PI5P interacts with two distant flexible linker regions of UHRF1 in a mode that is dependent on the polar head group and the acyl part of the phospholipid. The associated conformational rearrangements stably position the H3unmodified and H3K9me3 histone recognition modules of UHRF1 for multivalent and synergistic binding of the H3 tail. Our work highlights a novel molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.

The Role of Pulmonary Surfactant in COVID-19 Understanding

Background: In Covid-19 the virus infects the respiratory tract in human. When lung tissue becomes diseased, the walls and lining of the alveoli and capillaries are damaged. At this point lung compliance and ventilation decrease. Pulmonary surfactant that is produced and dispersed into alveolar space, has a significant role in understanding how heavily covid-19 interferes and infects lung cells. The importance of pulmonary surfactant in alveoli is to lower surface tension at air/liquid interface in the lung. This is achieved by reducing the work of breathing and preventing alveolar collapse. The main constituent of pulmonary surfactant is dipalmitoylphosphatidylcholine (DPPC) (C40H80NO8P). It is a phospholipid containing two non polar palmitic acid C16 chains as hydrophobic tails linked to a polar head group of a phosphatidylcholine (also known as lecithin). Rationale of the Review and Objective Method: When DPPC molecules are in contact with a polar solvent, micelles which grow further into bilayers are formed considering their cylindrical structures. This trait makes the whole structure of pulmonary surfactant as amphipathic and surface active molecules. The head group of phosphatidylcholine in the pulmonary surfactant is attracted by polar liquid molecules causing a reduction of the liquid surface tension. Conclusion: This review complements the quoted information analysing them theoretically and integrates recent advances in pulmonary surfactant research with the global pandemic.

Interactions of primaquine and chloroquine with PEGylated phosphatidylcholine liposomes

This study aimed to analyze the interaction of primaquine (PQ), chloroquine (CQ), and liposomes to support the design of optimal liposomal delivery for hepatic stage malaria infectious disease. The liposomes were composed of hydrogenated soybean phosphatidylcholine, cholesterol, and distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethyleneglycol]-2000), prepared by thin film method, then evaluated for physicochemical and spectrospic characteristics. The calcein release was further evaluated to determine the effect of drug co-loading on liposomal membrane integrity. The results showed that loading PQ and CQ into liposomes produced changes in the infrared spectra of the diester phosphate and carbonyl ester located in the polar part of the phospholipid, in addition to the alkyl group (CH2) in the nonpolar portion. Moreover, the thermogram revealed the loss of the endothermic peak of liposomes dually loaded with PQ and CQ at 186.6 °C, which is identical to that of the phospholipid. However, no crystallinity changes were detected through powder X-ray diffraction analysis. Moreover, PQ, with either single or dual loading, produced the higher calcein release profiles from the liposomes than that of CQ. The dual loading of PQ and CQ tends to interact with the polar head group of the phosphatidylcholine bilayer membrane resulted in an increase in water permeability of the liposomes.

Role of Intermolecular Forces on Surfactant-Steam Performance into Heavy Oil Reservoirs

Summary This study investigates the role of polar fractions of heavy oil in the surfactant-steamflooding process. Performance analyses of this process were done by examination of the dipole-dipole and ion-ion interactions between the polar head group of surfactants and the charged polar fraction of crude oil, namely, asphaltenes. Surfactants are designed to reduce the interfacial tension (IFT) between two immiscible fluids (such as oil and water) and effectively used for oil recovery. They reduce the IFT by aligning themselves at the interface of these two immiscible fluids; this way, their polar head group can stay in water and nonpolar tail can stay in the oil phase. However, in heavy oil, the crude oil itself has a high number of polar components (mainly asphaltenes). Moreover, the polar head group in surfactants is charged, and the asphaltene fraction of crude oils carries reservoir rock components with charges. The impact of these intermolecular forces on the surfactant-steam process performance was investigated with 10 coreflood experiments on an extraheavy crude oil. Nine surfactants (three anionic, three cationic, and three nonionic surfactants) were tested. Results of each coreflood test were analyzed through cumulative oil recovery and residual oil content. The performance differences were evaluated by polarity determination through dielectric constant measurements and by ionic charges through zeta potential measurements on asphaltene fractions of produced oil and residual oil samples. The differences in each group of surfactants tested in this study are the tail length. Results indicate that a longer hydrocarbon tail yielded higher cumulative oil recovery. Based on the charge groups present in the polar head of anionic surfactants resulted in higher oil recovery. Further examinations on asphaltenes from produced and residual oils show that the dielectric constants of asphaltenes originated from the produced oil, giving higher polarity for surfactant-steam experiments conducted with longer tail length, which provide information on the polarity of asphaltenes. The ion-ion interaction between produced oil asphaltenes and surfactant head groups were determined through zeta potential measurements. For the most successful surfactant-steam processes, these results showed that the changes on asphaltene surface charges were becoming lower with the increase in oil recovery, which indicates that once asphaltenes are interacting more with the polar head of surfactants, then the recovery rate increases. Our study shows that the surfactant-steamflooding performance in heavy oil reservoirs is controlled by the interaction between asphaltenes and the polar head group of surfactants. Accordingly, the main mechanism that controls the effectiveness of the process is the ion-ion interaction between the charges in asphaltene surfaces and the polar head group of crude oils. Because crude oils carry mostly negatively charged reservoir rock particles, our study suggests the use of anionic surfactants for the extraction of heavy oils.