Enhanced Potency of a Broad H7N9-Neutralizing Antibody HNIgGA6 Through Structure-Based Design.

H7N9 influenza virus was first isolated in 2013 and has caused five epidemic waves among humans to date. Treatment opinions are currently limited. Previously, we characterized a human neutralizing antibody, HNIgGA6, by isolating rearranged heavy- and light-chain genes from convalescent patients. The mAb disrupts viral attachment to the cellular receptor by directly interposing into the receptor binding site (RBS) and broadly neutralizing divergent H7N9 strains. To increase the protective efficacy of HNIgGA6, we employed a structure-based design to enhance its binding affinity and neutralization potency. When the serine at position 28 on light-chain complementarity-determining region 1 (LCDR1) was substituted by a histidine, compared to HNIgGA6, the mutated antibody showed an approximately three-fold increase in HA-binding affinity and 10-fold enhancement in neutralization potency in vitro. Importantly, the S28H variant also exhibited broad H7N9-neutralizing activity. When administered to BALB/c mice, mAb S28H showed enhanced potency in inhibiting the pulmonary virus titre and reducing lung lesions and resulted in better protection of the animals than did the original antibody.

Structural characterization of glycinamide-RNase-transformylase T from Mycobacterium tuberculosis.

Enzymes from the purine salvage pathway in Mycobacterium tuberculosis (Mtb) have been regarded as an attractive target for the development of anti-bacterial drugs. Although this pathway has not been extensively studied in Mtb, it has been identified as essential for growth and survival. Glycinamide-RNase-transformylase T (PurT) is found only in some specific bacteria including Mtb and utilizes ATP-dependent ligation to catalyze the formylation of 5'-phosphoribosyl-glycinamide (GAR) in the third reaction of the de novo purine salvage pathway. In the study, we determined the crystal structure of MtbPurT at a resolution of 2.79 Å. In contrast to Pyrococcus horikoshii OT3 PurT (phBCCPPurT), MtbPurT exhibits an "open" conformation, which results in a broader ATP-binding pocket and thus might facilitate the entry and exit of the cofactor. Additionally, active site superposition with E.coli PurT (EcPurT) showed that residues involved in the ATP-binding site in MtbPurT exhibited structural similarity but had notable difference in the GAR-binding site. The loop 383-389 in MtbPurT was much shorter and shifted 5.7 Å away from the phosphate of the GAR substrate. The different GAR-binding mode might result in a large conformational change in MtbPurT, and would provide a possible opportunity for anti-TB drug development.

Broad neutralizing activity of a human monoclonal antibody against H7N9 strains from 2013 to 2017.

H7N9 influenza virus has been circulating among humans for five epidemic waves since it was first isolated in 2013 in China. The recent increase in H7N9 infections during the fifth outbreak in China has caused concerns of a possible pandemic. In this study, we describe a previously characterized human monoclonal antibody, HNIgGA6, obtained by isolating rearranged heavy-chain and light-chain genes from patients who had recovered from H7N9 infections. HNIgGA6 recognized multiple HAs and neutralized the infectivity of 11 out of the 12 H7N9 strains tested, as well as three emerging HPAI H7N9 isolates. The only resistant strain was A/Shanghai/1/2013 (H7N9-SH1), which carries the avian receptor alleles 186V and 226Q in the sialic acid-binding pocket. The mAb broadly neutralized divergent H7N9 strains from 2013 to 2017 and represents a potential alternative treatment for H7N9 interventions.

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide.

Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and ¹H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.

Silencing of DNA repair sensitizes pediatric brain tumor cells to γ-irradiation using gold nanoparticles.

We present a nanoparticle (NP)-mediated delivery vehicle that effectively carries and protects siRNA in pediatric ependymoma (EP) and medulloblastoma (MB) cells. The delivery vehicle consists of gold NPs coated with a polymeric shell comprising polyethylene glycol (PG), chitosan and polyethyleneimine (Au-CP-PEI). NPs loaded with siRNA knocked down Ape1 expression by over 75% in both MB and EP cells. Further, this reduction in Ape1 expression is associated with an increase in DNA damage after irradiation. The results indicate that NP-associated delivery of siApe1 is a feasible approach to circumventing pediatric brain tumor resistance to radiation therapy.

Magnetic nanoparticles modified with quaternarized N-halamine based polymer and their antibacterial properties.

We present a simple and facile approach for preparing antibacterial magnetic nanoparticles, which were modified with quaternarized N-halamine based cationic polymer (CPQN). The CPQN functionalized magnetic nanoparticles (MNPs-CPQN) were characterized by X-ray photoelectron spectra, Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, and thermogravimetric analysis. Antibacterial properties were investigated with Gram positive bacteria S. aureus and Gram negative bacteria E. coli. Antibacterial assessment showed that the MNPs-CPQN could eliminate nearly 100% of S. aureus and 99.9% of E. coli (10(7-8) CFU/mg nanoparticles) in 5 min, while the bactericide rate of quaternized N-halamine precursor based cationic polymer coated magnetic nanoparticles (MNPs-CPQNP) were 99.6 and 95.2%, respectively. The prepared nanoparticles exhibited a good response to an external magnetic field and had a saturation magnetization of 36.6 emu g(-1). On the basis of their excellent antibacterial properties and magnetic responsiveness, the MNPs-CPQN would be a promising antibacterial material for water disinfection.

An Effective Synthesis Method for Tilorone Dihydrochloride with Obvious IFN-α Inducing Activity.

Tilorone dihydrochloride (1) has great potential for inducing interferon against pathogenic infection. In this paper, we describe a convenient preparation method for 2,7-dihydroxyfluoren-9-one (2), which is a usual pharmaceutical intermediate for preparing tilorone dihydrochloride (1). In the novel method, methyl esterification of 4,4'-dihydroxy-[1,1'-biphenyl]-2-carboxylic acid (4) was carried out under milder conditions with higher yield and played an important role in the preparation of compound 2. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS, and ¹H-NMR. Furthermore, the synthesized tilorone dihydrochloride exhibited an obvious effect on induction of interferon-α (IFN-α) in mice within 12 h, and the peak level was observed until 24 h. This fruitful work has resulted in tilorone dihydrochloride becoming available in large-scale and wide application in clinics, which has a good pharmaceutical development prospects.

Synthesis and catalytic properties of a series of cobalt porphyrins as cytochrome P450 model: the effect of substituents on the catalytic activity.

A series of cobalt porphyrins derived from hemin was prepared as cytochrome P450 models. Effects of substituents at the cobalt deuteroporphyrin-propionate side chains are investigated in oxidation of toluene with air to benzaldehyde and benzyl alcohol without the use of solvent and sacrificial co-reductant. The catalytic activity of cobalt porphyrins depends on the type of substituents. When the electron-withdrawing groups like -Cl, -Br, were introduced into the double propionate side chains, they can increase the catalyst stability and selectivity to benzaldehyde. In comparison with these electron-withdrawing groups, the electron-donor groups, such as -CH3, -S-S- and -NH2 groups, can improve their catalytic activities. Moreover, the electron-donor group containing an unpaired electron (such as -S-S-, -NH2) is benefit for improving its catalytic efficiency and promoting the electron delivery. It can be concluded that the double propionate side chains in the deuteroporphyrin complex may participate in oxidation process and effect electron transfer from the high-valent metalloporphyrin species to the substrate.

[Color features of fluorescent image for cervix cancer and its judgments].

Fluorescent image of human mucous can display a special color to demonstrate a cancer at its early stage. This will provide a novel method for early diagnose of the Pathological Changes. This research firstly extracted the color characteristics of the clinic images and then calculated all RGB components in different local areas. Finally, a stability analysis was performed. On the above basis we showed a conclusion that G/R can be used as a judge index for pathologic changes.

Investigations on the demetalation of metalloporphyrins under ultrasound irradiation.

An efficiently facile method for the demetalation from metalloporphyrins has been developed, which uses high-intensity ultrasound to initiate the ligand dissociation in a mixed solvent of (CH(3)CO)(2)O/HCl with FeSO(4). The influences of substituents, bath temperature and reaction time on the reactions were also investigated, on the base of which the mechanism of demetalation and the effect of ultrasound irradiation on metal-ligand cleavage have been discussed in detail.

A facile synthesis of deuteroporphyrins derivatives under ultrasound irradiation.

A facile, efficient and general method for preparing deuteroporphyrin derivatives by using concentrated H(2)SO(4) and alcohol under ultrasound irradiation has been developed. A series of new deuteroporphyrin derivatives bearing different propionic ester groups have been synthesized in good yields starting from readily accessible deuterohemin. The characterization of these compounds confirms the synthetic methodology. Compared with conventional methods, the main advantages of the present procedure are shorter reaction time and higher yields.

[Combustion temperature measurement of pyrotechnic composition using remote sensing Fourier transform infrared spectrometry].

In this paper, combustion characterization of pyrotechnic composition is investigated using a remote sensing Fourier transform infrared spectrometry. The emission spectra have been recorded between 4,700 and 740 cm-1 with a spectral resolution of 4 cm-1. The combustion temperature can be determined remotely from spectral line intensity distribution of the fine structure of the emission fundamental band of gaseous products such as HF. The relationship between combustion temperature and combustion time has been given. Results show that there is a violent mutative temperature field with bigger temperature gradient near combustion surface. It reveals that the method of temperature measurement using remote sensing FTIR for flame temperature of unstable, violent and short time combustion on real time is a rapid, accurate and sensitive technique without interference the flame temperature field. Potential prospects of temperature measurement, gas product concentration measurement and combustion mechanism are also revealed.