Science in China Series B: Chemistry

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2+ ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.

To increase the in vivo stability of polycation gene carriers, a pH-sensitive shielding system, γ-benzyl l-glutamate-co-glutamate acid polymer (PGA(60) (60 refers to the molar ratio of glutamate acid in the polymer)), was synthesized and characterized. PGA(60) showed pH sensitivity at about pH 6.0. PGA(60) shielded the positive charge of DNA/PEI (1:1) complexes. Gel retardation assay showed that no DNA-strand exchange with PGA(60) occurred after PGA(60) was added to DNA/PEI complexes at different proportions. MTT cytotoxicity tests demonstrated that neither PGA(60) nor DNA/PEI/PGA(60) ternary complexes had cytotoxicity at the test concentration. The transfection efficiency was improved when the positive charge was partly shielded by PGA(60). Because of the charge repulsion between the surface of cells and ternary complex particles, there was almost no transfection efficiency when the zeta potential of ternary complexes turned to negative. Because of the suitable pH sensitive range, PGA(60) may be a potential shielding system for polycation gene carriers to be used in vivo.

Uniting dual-modality of fluorescence and photoacoustic (PA) imaging into theranostic nanoprobes is imperative for spatio-temporally tracking of drug delivery, distribution, and release. Herein, we present a rational design strategy of molecularly precise amphiphilic prodrugs BPn-Cy-S-CPT (n=0, 5, and 20, refers to the degree of polyethylene glycol (PEG) polymerization; CPT=camptothecin) to tune their self-assembly behaviour, innovatively integrating dual-modal PA and near-infrared (NIR) fluorescence imaging in a single-molecular framework. Among these elaborately designed prodrugs, it is found that only BP20-Cy-S-CPT could form uniform and highly stable self-assemblies, especially in showing synergistically enhanced PA and dual-channel NIR signals. In detail, PA signal is employed to trace the in vivo delivery with high spatial resolution, meanwhile the glutathione (GSH)-triggered dual-channel fluorescence response could real-timely monitor drug distribution and release without “blind spot”. The results of in vivo dual-modal PA/NIR imaging have verified that BP20-Cy-S-CPT displayed synergistic targeting (including passive, active, and activatable targeting) for tumor-specific delivery, and thereby executed CPT release in the tumor site. Consequently, our molecularly precise BP20-Cy-S-CPT self-assemblies could make a breakthrough to spatio-temporally track the in vivo drug release profile, expanding the intelligent theranostic toolbox for precise cancer treatment.

The creation of artificial enzymes to mimic natural enzymes remains a great challenge owing to the complexity of the structural arrangement of the essential amino acids in catalytic centers. In this study, we used the phosphatase-based enzyme-instructed self-assembly (EISA) to supervise artificial esterases’ final structures and catalytic activities. We reported that peptide precursors containing different phosphorylation sites could preorganize into alternated nanostructures and undergo dephosphorylation in the presence of alkaline phosphatase (ALP) with variation in kinetic and thermodynamic profiles. Although identical self-assembly compositions were formed after dephosphorylation, precursors with more enhanced preorganized states tended to better promote ALP dephosphorylation, facilitate further self-assembly, and strengthen the catalytic activities of the final assemblies. We envisioned that our strategy would be useful for further construction and manipulation of various artificial enzymes with superior catalytic activities.

A microfluidic device to control single crystallization on the micron scale has been developed. The salt solution was stored in the nano-volume gaps between the arrays of protrudent circular plots in the microchip. The mixed organic solvent was injected into the chip as the counter diffusion phase for crystallization forming. This device provides a liquid-liquid interface through which only one phase flows while the other stays at the fixed plot. Therefore, it is possible to control the position of crystallization on the fixed plot. We can control the size and the uniformity of single crystals from 5 to 50 μm in length by adjusting the relative factors, such as interface lifetime, breeds of the mix-organic solvents and injecting velocities. The longer interface lifetime and lower organic solvent injecting velocities can bring up larger and more asymmetric crystals, which nearly shows the same trend compared with the macroscopic crystallization. Finally, the effect of the surfactant on the crystallization in the micro-device was studied. By adding the surfactant into the liquid-liquid interface, smaller sizes of crystals can be obtained without changing the crystal configuration.

A highly enantioselective 1,3-dipolar cycloaddition of α-substituted diazoesters with exocyclic enones was achieved with chiral scandium(III)/N,N’-dioxide complex as the catalyst. This protocol provided a facile and efficient route to optically active 1-pyrazoline-based spirochromanones and others with good outcomes (up to 97% yield, 98% ee with >95:5 dr). Moreover, enantioenriched 2-pyrazoline-based spirochromanones were also accessible by switching α-substituted diazoesters to α-diazoacetates. The further specific transformations of chiral pyrazoline-based spiro-compounds to spirocyclopropane derivatives were disclosed as well.

Developing stable electrodes for seawater splitting remains a great challenge due to the detachment of catalysts at a large operating current and severe anode corrosion caused by chlorine. Herein, divalent anion intercalation and etching-hydrolysis strategies are deployed to synthesize the ultra-stable anode, dendritic Fe(OH)3 grown on Ni(SO4)0.3(OH)1.4-Ni(OH)2. Experimental results reveal that the anode exhibits good activity and excellent stability in alkaline simulated seawater. After 500 h, the current density operated at 1.72 V remains 99.5%, about 210 mA cm−2. The outstanding stability originates from the etching-hydrolysis strategy, which strengthens the interaction between the catalyst and the carrier and retards thus the detachment of catalysts at a large current density. Besides, theoretical simulations confirm that the intercalated divalent anions, such as SO 4 2− and CO 3 2− , can weaken the adsorption strength of chlorine on the surface of catalysts and hinder the coupling and hybridization between chlorine and nickel, which slows down the anode corrosion and improves catalytic stability. Furthermore, the two-electrode system shows the remarkable 95.1% energy efficiency at 2,000 A m−2 and outstanding stability in 6 mol L−1 KOH + seawater at 80 °C.