Discovery of selective, small-molecule inhibitors of RNA complexes--I. The Tat protein/TAR RNA complexes required for HIV-1 transcription

We have developed a therapeutic program focusing on the inhibition of a human immunodeficiency virus-1 specific protein-RNA interaction. This program begins with a search for small organic molecules that would interfere with the binding of Tat protein to TAR RNA. The methodologies chosen to study the HIV-1 Tat-TAR interaction and inhibition include gel mobility shift assays, scintillation proximity assays, filtration assays, and mass spectrometry. These methods helped establish in vitro high-throughput screening assays which rapidly identified Tat-TAR inhibitors from our corporate compound library. Tat-activated reporter gene assays were then used to investigate the cellular activities of the Tat-TAR inhibitors. The cellular activity, selectivity, and toxicity data for select Tat-TAR inhibitors were determined. Evaluation of both the cellular data and the Tat-TAR inhibition results led to further testing in anti-HIV-1 infection assays.     

Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules

More than 50 new inhibitors of the oncogenic Stat3 protein were identified through a structure–activity relationship (SAR) study based on the previously identified inhibitor S3I‐201 (IC₅₀=86 μM , K_i>300 μM ). A key structural feature of these inhibitors is a salicylic acid moiety, which, by acting as a phosphotyrosine mimetic, is believed to facilitate binding to the Stat3 SH2 domain. Several of the analogues exhibit higher potency than the lead compound in inhibiting Stat3 DNA binding activity, with an in vitro IC₅₀ range of 18.7–51.9 μM , and disruption of Stat3–pTyr peptide interactions with K_i values in the 15.5–41 μM range. One agent in particular exhibited potent inhibition of Stat3 phosphorylation in both breast and multiple myeloma tumor cells, suppressed the expression of Stat3 target genes, and induced antitumor effects in tumor cells harboring activated Stat3 protein.     

Effect of peeling and unpeeling on yield,chemical structure,morphology and pasting properties of starch extracted from three diverse potato cultivars of Pakistan

The current study investigates the comparison and quality characteristics of starches isolated from potatoes using different processing methods from three commercial varieties: Lady Rosetta, Asterix and Challenger, for the first time in Pakistan. The analysis of variance revealed that starch yield significantly (P < 0.05) depended on total solids, peeling (12.7%, 12.0% and 12.0%) and unpeeling (15.0%, 14.0% and 14.0%) of potatoes compared to potato varieties for Lady Rosetta, Challenger and Asterix, respectively. Moreover, pasting properties, protein content, redness and yellowness were increased in those starches isolated without peeling while carbohydrates and lightness were increased in peeled potato starches. Furthermore, Fourier-transform infrared spectroscopy analysis revealed that protein (1200–1400 cm⁻¹) was present in starch extracted without peeling. Besides, scanning electron microscopy analysis revealed oval-shaped starch granules with no impurities in peeled potato starch. The findings suggest the suitability of peeling process for obtaining a high-quality pure starch.     

2,2'-Dithiobisbenzamides and 2-benzisothiazolones, two new classes of antiretroviral agents: SAR and mechanistic considerations

Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.     

The effect of acetylation on the crystallinity of BC/CNTs nanocomposite

BACKGROUND: Bacterial cellulose (BC) synthesized by Acetobacter xylinum has been shown to be a potential matrix for impregnating carbon nanotubes (CNTs) to produce bacterial cellulose/carbon nanotubes (BC/CNTs) nanocomposite. The objective of this study was to investigate the crystal structure of BC/CNTs nanocomposite after acetylation treatment. Approximately 0.05 w/v% CNTs were added onto continuously developed BC. Then, the BC/CNTs nanocomposite was acetylated heterogeneously. RESULTS: The crystallinity characteristic of formed BC/CNTs acetate was analyzed using an X‐ray diffractometer (XRD). The crystallization index (CrI) of BC/CNTs acetate was better than BC acetate, i.e. 97:3 and 93:7, respectively. The crystallite size of BC microfibrils in BC/CNTs sheet was reduced because of the impregnated CNTs. However, the reduction of crystallite size for BC/CNTs acetate was lower than that of BC acetate showing that the existence of CNTs within BC micofibrils had protected the BC crystal structure from further destruction by acetylating agent. CONCLUSION: CNTs is a powerful substance that acted as a void filler between BC crystalline structure and protected the nano‐biocomposite from total degradation by the acetylation process. Copyright © 2011 Society of Chemical Industry     

Cultural Exchange and Urban Appropriation: Spaces for Art in Sharjah's Historical Centre

There is a common misconception that culture in the Gulf must be entirely newly imported and artificial. Architect Mona El Mousfy and architect and researcher Sharmeen Syed , who have both been engaged as architects for the Sharjah Art Foundation Art Spaces project and the Sharjah Biennial, challenge the notion of ‘constructed heritage’ at Sharjah in UAE. They show Sharjah to be a highly adaptive, historically multiethnic city that is characterised by its cultural fluidity.