Discovery of Dengue Virus Inhibitors.

To date, there is still no approved anti-dengue agent to treat dengue infection in the market. Although the only licensed dengue vaccine, Dengvaxia is available, its protective efficacy against serotypes 1 and 2 of dengue virus was reported to be lower than serotypes 3 and 4. Moreover, according to WHO, the risk of being hospitalized and having severe dengue increased in seronegative individuals after they received Dengvaxia vaccination. Nevertheless, various studies had been carried out in search of dengue virus inhibitors. These studies focused on the structural (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) of dengue virus as well as host factors as drug targets. Hence, this article provides an overall up-to-date review of the discovery of dengue virus inhibitors that are only targeting the structural and non-structural viral proteins as drug targets.

Polyethylene glycol-coated porous magnetic nanoparticles for targeted delivery of chemotherapeutics under magnetic hyperthermia condition.

PURPOSE: Although magnetite nanoparticles (MNPs) are promising agents for hyperthermia therapy, insufficient drug encapsulation efficacies inhibit their application as nanocarriers in the targeted drug delivery systems. In this study, porous magnetite nanoparticles (PMNPs) were synthesized and coated with a thermosensitive polymeric shell to obtain a synergistic effect of hyperthermia and chemotherapy. MATERIALS AND METHODS: PMNPs were produced using cetyltrimethyl ammonium bromide template and then coated by a polyethylene glycol layer with molecular weight of 1500 Da (PEG1500) and phase transition temperature of 48 ± 2 °C to endow a thermosensitive behavior. The profile of drug release from the nanostructure was studied at various hyperthermia conditions generated by waterbath, magnetic resonance-guided focused ultrasound (MRgFUS), and alternating magnetic field (AMF). The in vitro cytotoxicity and hyperthermia efficacy of the doxorubicin-loaded nanoparticles (DOX-PEG1500-PMNPs) were assessed using human lung adenocarcinoma (A549) cells. RESULTS: Heat treatment of DOX-PEG1500-PMNPs containing 235 ± 26 mg·g-1 DOX at 48 °C by waterbath, MRgFUS, and AMF, respectively led to 71 ± 4%, 48 ± 3%, and 74 ± 5% drug release. Hyperthermia treatment of the A549 cells using DOX-PEG1500-PMNPs led to 77% decrease in the cell viability due to the synergistic effects of magnetic hyperthermia and chemotherapy. CONCLUSION: The large pores generated in the PMNPs structure could provide a sufficient space for encapsulation of the chemotherapeutics as well as fast drug encapsulation and release kinetics, which together with thermosensitive characteristics of the PEG1500 shell, make DOX-PEG1500-PMNPs promising adjuvants to the magnetic hyperthermia modality.

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): a review.

Hindered phenols find a wide variety of applications across many different industry sectors. Butylated hydroxytoluene (BHT) is a most commonly used antioxidant recognized as safe for use in foods containing fats, pharmaceuticals, petroleum products, rubber and oil industries. In the past two decades, there has been growing interest in finding novel antioxidants to meet the requirements of these industries. To accelerate the antioxidant discovery process, researchers have designed and synthesized a series of BHT derivatives targeting to improve its antioxidant properties to be having a wide range of antioxidant activities markedly enhanced radical scavenging ability and other physical properties. Accordingly, some structure-activity relationships and rational design strategies for antioxidants based on BHT structure have been suggested and applied in practice. We have identified 14 very sensitive parameters, which may play a major role on the antioxidant performance of BHT. In this review, we attempt to summarize the current knowledge on this topic, which is of significance in selecting and designing novel antioxidants using a well-known antioxidant BHT as a building-block molecule. Our strategy involved investigation on understanding the chemistry behind the antioxidant activities of BHT, whether through hydrogen or electron transfer mechanism to enable promising anti-oxidant candidates to be synthesized.

PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives.

New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 µM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.

Current approaches in antiviral drug discovery against the Flaviviridae family.

Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed.

Improved scFv anti-HIV-1 p17 binding affinity guided from the theoretical calculation of pairwise decomposition energies and computational alanine scanning.

Computational approaches have been used to evaluate and define important residues for protein-protein interactions, especially antigen-antibody complexes. In our previous study, pairwise decomposition of residue interaction energies of single chain Fv with HIV-1 p17 epitope variants has indicated the key specific residues in the complementary determining regions (CDRs) of scFv anti-p17. In this present investigation in order to determine whether a specific side chain group of residue in CDRs plays an important role in bioactivity, computational alanine scanning has been applied. Molecular dynamics simulations were done with several complexes of original scFv anti-p17 and scFv anti-p17mutants with HIV-1 p17 epitope variants with a production run up to 10 ns. With the combination of pairwise decomposition residue interaction and alanine scanning calculations, the point mutation has been initially selected at the position MET100 to improve the residue binding affinity. The calculated docking interaction energy between a single mutation from methionine to either arginine or glycine has shown the improved binding affinity, contributed from the electrostatic interaction with the negative favorably interaction energy, compared to the wild type. Theoretical calculations agreed well with the results from the peptide ELISA results.

The impact of local surface changes in Borneo on atmospheric composition at wider spatial scales: coastal processes, land-use change and air quality.

We present results from the OP3 campaign in Sabah during 2008 that allow us to study the impact of local emission changes over Borneo on atmospheric composition at the regional and wider scale. OP3 constituent data provide an important constraint on model performance. Treatment of boundary layer processes is highlighted as an important area of model uncertainty. Model studies of land-use change confirm earlier work, indicating that further changes to intensive oil palm agriculture in South East Asia, and the tropics in general, could have important impacts on air quality, with the biggest factor being the concomitant changes in NO(x) emissions. With the model scenarios used here, local increases in ozone of around 50 per cent could occur. We also report measurements of short-lived brominated compounds around Sabah suggesting that oceanic (and, especially, coastal) emission sources dominate locally. The concentration of bromine in short-lived halocarbons measured at the surface during OP3 amounted to about 7 ppt, setting an upper limit on the amount of these species that can reach the lower stratosphere.

N'-[(Biphenyl-4-yl)methyl-ene]-2-[(3,5-di-tert-butyl-4-hydroxy-benz-yl)sulfan-yl]acetohydrazide.

In the title compound, C(30)H(36)N(2)O(2)S, the dihedral angle between the two aromatic rings of the biphenyl residue is 31.2 (1)°. The two methyl-ene C atoms subtend an angle of 99.9 (1)° at the S atom. In the crystal, mol-ecules form inversion dimers linked by pairs of N-H⋯O hydrogen bonds. The hydroxyl group is shielded by the tert-butyl residues and is therefore not involved in any hydrogen bonding.

2-[4-Acetyl-5-(biphenyl-4-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]phenyl acetate.

In the title mol-ecule, C(24)H(20)N(2)O(4), the five-membered oxadiazole ring is nearly planar (r.m.s. deviation = 0.053 Å) and the phenyl ring of the biphenyl unit attached to it forms a dihedral angle of 73.2 (1)°; the other phenyl ring is close to coplanar with the oxadiazole ring [dihedral angle = 6.2 (2)°].

Dipyridinium 2,2'-dithio-dinicotinate.

The dianion of the title salt, 2C(5)H(6)N(+)·C(12)H(6)N(2)O(4)S(2) (2-), lies on a special position of 2 site symmetry that relates one thio-nicotinate part to the other, and the dihedral angle between the niotinate planes is 89.2 (2)°. The pyridinium cations are hydrogen bonded to the carboxyl-ate group by way of N-H⋯O links.

4-Chloro-2-[(E)-2-(4-methoxy-phen-yl)ethyl-imino-meth-yl]phenol.

In the title Schiff base, C(16)H(16)ClNO(2), the 2-(4-methoxy-phen-yl)ethyl (CH(3)OC(6)H(4)CH(2)CH(2)-; r.m.s. deviation = 0.10 Å) and 4-chloro-2-(imino-meth-yl)phenol (N=CHC(6)H(3)ClOH; r.m.s. deviation = 0.01 Å) portions are both essentially planar, the two parts being inclined at an angle of 61.8 (1)°. The hydroxy group forms a hydrogen bond to the imino N atom.

2-(3,5-Di-tert-butyl-4-hydroxy-benzyl-sulfan-yl)-N'-(3-methoxy-benzyl-idene)acetohydrazide.

The title compound, C(25)H(34)N(2)O(3)S, is a derivative of N'-benzyl-ideneacetohydrazide having substituents on the acetyl and benzylidenyl parts, and displays a planar C(carbon-yl)-NH-NC(anis-yl) fragment [torsion angle = 174.9 (3)°]. The -NH- unit forms an N-H⋯O hydrogen bond with the carbonyl O atom of an inversion-related mol-ecule.

Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites.

A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.

Pheophorbide b ethyl ester from a chlorella vulgaris dietary supplement.

In the title compound, C(37)H(38)N(4)O(6), four five-membered nitro-gen-bearing rings are nearly coplanar. Two N atoms in two these five-membered rings have attached H atoms, which contribute to the formation of intra-molecular N-H⋯N hydrogen bonds [N⋯N = 2.713 (5)-3.033 (6) Å].

2-(3,5-Di-tert-butyl-4-hydroxy-benzyl-sulfan-yl)nicotinic acid.

Two mol-ecules of the title compound, C(21)H(27)NO(3)S, are disposed about a center of inversion, generating an O-H⋯O hydrogen-bonded dimer.

Di-n-butyl-ammonium 2-(3,5-di-tert-butyl-4-hydroxy-benzyl-sulfan-yl)nicotinate.

The asymmetric unit of the title compound, C(8)H(20)N(+)·C(21)H(26)NO(3)S(-), contains two indpendent ion pairs which are disposed about a psuedo-inversion center, generating an ammonium-carboxylate N-H⋯O hydrogen-bonded four-component cluster. In the crystal structure, adjacent clusters are linked by hydr-oxy-carboxylate O-H⋯O hydrogen bonds, forming a chain.

N-Acetyl-2-hydroxy-N'-[methoxy(1-methylindol-2-yl)methyl]benzohydrazide.

In the crystal structure of the title Schiff-base, C(20)H(21)N(3)O(4), the amino group forms an N-H⋯O hydrogen bond to the acetyl group of an adjacent mol-ecule, forming a zigzag chain. The 2-hydr-oxy group is inter-nally hydrogen bonded to the amido group though an O-H⋯O hydrogen bond.

The full-length clone of cucumber green mottle mosaic virus and its application as an expression system for Hepatitis B surface antigen.

A cucumber green mosaic mottle virus (CGMMV) full-length clone was developed for the expression of Hepatitis B surface antigen (HBsAg). The expression of the surface displayed HBsAg by the chimeric virus was confirmed through a double antibody sandwich ELISA. Assessment of the coat protein composition of the chimeric virus particles by SDS-PAGE analysis showed that 50% of the coat proteins were fused to the HBsAg. Biological activity of the expressed HBsAg was assessed through the stimulation of in vitro antibody production by cultured peripheral blood mononuclear cells (PBMC). PBMC that were cultured in the presence of the chimeric virus showed up to an approximately three-fold increase in the level of anti HBsAg immunoglobulin thus suggesting the possible use of this new chimeric virus as an effective Hepatitis B vaccine.

Computational docking of L-arginine and its structural analogues to C-terminal domain of Escherichia coli arginine repressor protein (ArgRc).

The arginine repressor (ArgR) of Escherichia coli binds to six L-arginine molecules that act as its co-repressor in order to bind to DNA. The binding of L-arginine molecules as well as its structural analogues is compared by means of computational docking. A grid-based energy evaluation method combined with a Monte Carlo simulated annealing process was used in the automated docking. For all ligands, the docking procedure proposed more than one binding site in the C-terminal domain of ArgR (ArgRc). Interaction patterns of ArgRc with L-arginine were also observed for L-canavanine and L-citrulline. L-lysine and L-homoarginine, on the other hand, were shown to bind poorly at the binding site. Figure A general overview of the sites found from docking the various ligands into ArgRc ( grey ribbons). Red coloured sticks: residues in binding site H that was selected for docking