Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic Kd approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors

Brettanomyces bruxellensis yeasts: impact on wine and winemaking

Yeasts belonging to the Brettanomyces/Dekkera genus are non-conventional yeasts, which affect winemaking by causing wine spoilage all over the world. This mini-review focuses on recent results concerning the presence of Brettanomyces bruxellensis throughout the wine processing chain. Here, culture-dependent and independent methods to detect this yeast on grapes and at the very early stage of wine production are encompassed. Chemical, physical and biological tools, devised for the prevention and control of such a detrimental species during winemaking are also presented. Finally, the mini-review identifies future research areas relevant to the improvement of wine safety and sensory profiles

Novobiocin–ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition.

A series of tailored novobiocin–ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a–c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90)

The impact of different barrel sanitation approaches on the spoilage microflora and phenols composition of wine

Careful control of spoilage microflora inside wine containers is a key issue during winemaking. To date, attention has been paid to the development of an effective protocol for the eradication of spoilage agents, especially Brettanomyces, from barrels. Few studies have taken into account the modifications caused by sanitation treatments in wine and wood barrels. In the present study the effects of two sanitation treatments (ozone and sodium hydroxide) on barrel spoilage microflora and the composition of the wine stored inside them were evaluated. The phenols of wine (38 compounds) were characterised using a UHPLC–MS during the first 3 months of wine ageing, to see possible alterations in composition due to the chemical exchange from wood to wine in presence of sanitising agents. With the same scope, a panel of 13 judges carried out sensorial analysis of wines. The results showed that the tested treatments had little effect on the organoleptic characteristics of wines, but underline the different performance of the sanitation treatments in terms of eradicating microorganisms

Analysis of grapes and the first stages of the vinification process in wine contamination with Brettanomyces bruxellensis

Brettanomyces bruxellensis is a major cause of wine spoilage due to the production of ethyl phenols, and it has become a major worldwide oenological concern in recent years. The most critical factor in volatile phenol production is the presence of microorganisms responsible for biosynthesis. In this work, carried out during three consecutive harvests, grapes and the first step in grape processing (stemmingcrushing) have been evaluated as the origin of wine contamination by these spoilage yeasts. Results showed that there was nil or minimal presence of Brettanomyces yeasts in grapes and on the stemmer, in levels that the method was not able to detect. This shows that the main contamination of wines by this microorganism occurs in later stages of the vinification process and/or during storage. The contamination of many wines with Brettanomyces, either via the fruit or from the winery environment, during the early stages of vinification and before the start of aging, was confirmed by analyzing 100 recently made red wines, in which this yeast was detected in a high percentage of wines (27 %). However, the level of Brettanomyces yeasts found in the samples was low, with values which would not be sufficient to cause organoleptic defects. Consequently, this study confirms that many wines are still tainted by Brettanomyces when the winemaking phase comes to an end. It was also found that wines with problems during fermentation had a higher level of Brettanomyces. This is why it is essential to ensure strict controls during fermentation processes and conservation to prevent wine becoming spoiled or tainted