Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

Withanolides constitute a well-known family of plant-based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.     

Mannose‐based graft polyesters with tunable binding affinity to concanavalin A

Glycopolymers have been widely used to understand the interactions between carbohydrates and lectins, which facilitate the diagnosis and detection of disease and pathogens as well as the development of vaccines. While studies have been focused on the correlation of glycopolymer structure and their binding to lectins, graft‐type glycopolyesters are uncommon. Herein, we report the design and synthesis of mannose‐based graft polyesters by “grafting‐from” method and investigate their interactions with Concanavalin A (Con A). As confirmed by ¹H NMR spectroscopy and sulfuric acid‐UV method, graft polyesters with different lengths of mannose graft were successfully synthesized. Our results from turbidimetry binding assay showed that graft polyesters with longer mannose graft exhibit higher initial binding rate (k_i). Isothermal titration calorimetry measurements of these graft polyesters with Con A showed that polymers exhibit higher binding affinity (k_a) with the number of side chain mannose. This study provides understanding of the interaction between Con A and mannose‐based graft polyesters, which can be employed for the development of glycopolymeric therapeutics. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 3908–3917     

基于电化学传感器检测赭曲霉毒素A的研究进展

赭曲霉毒素A(Ochratoxin A,OTA)是一种由赭曲霉、青霉菌等真菌产生的次级代谢产物,在自然界分布广泛,具有肝毒性、肾毒性、致癌、致突变作用.鉴于其危害的严重性和污染的广泛性,发展高灵敏度的OTA检测技术引起了研究者的广泛关注.该文阐述了近年来新型电化学传感技术在OTA检测方面的发展及应用,全面综述了目前OT...     

Structure elucidation of triglycerides by chromatographic techniques. Part 1: Capillary GC of ozonized triglycerides

Structure determination of triglycerides according to their number of unsaturated fatty acids (N.U.F.A.) is more easily achieved after ozonolysis of their mixtures (fats and oils) than by capillary gas chromatographic analysis of the mixture as such. Analyses performed before and after ozonolysis of cocoa buttel, hazelnut oil, and a mixture of both fats illustrate the potential of this approach to the structure elucidation of triglycerides by chromatographic techniques.     

Ingenuity in performing replica permutation: How to order the state labels for improving sampling efficiency

In the replica-permutation method, an advanced version of the replica-exchange method, all combinations of replicas and parameters are considered for parameter permutation, and a list of all the combinations is prepared. Here, we report that the temperature transition probability depends on how the list is created, especially in replica permutation with solute tempering (RPST). We found that the transition probabilities decrease at large replica indices when the combinations are sequentially assigned to the state labels as in the originally proposed list. To solve this problem, we propose to modify the list by randomly assigning the combinations to the state labels. We performed molecular dynamics simulations of amyloid-β(16–22) peptides using RPST with the “randomly assigned” list (RPST-RA) and RPST with the “sequentially assigned” list (RPST-SA). The results show the decreases in the transition probabilities in RPST-SA are eliminated, and the sampling efficiency is improved in RPST-RA.     

ATP-Independent and Cell-Free Biosynthesis of β-Hydroxy Acids Using Vinyl Esters as Smart Substrates

In vitro biosynthetic pathways that condense and reduce molecules through coenzyme A (CoASH) activation demand energy and redox power in the form of ATP and NAD(P)H, respectively. These coenzymes must be orthogonally recycled by ancillary reactions that consume chemicals, electricity, or light, impacting the atom economy and/or the energy consumption of the biosystem. In this work, we have exploited vinyl esters as dual acyl and electron donor substrates to synthesize β-hydroxy acids through a non-decarboxylating Claisen condensation, reduction and hydrolysis stepwise cascade, including a NADH recycling step, catalyzed by a total of 4 enzymes. Herein, the chemical energy to activate the acyl group with CoASH and the redox power for the reduction are embedded into the vinyl esters. Upon optimization, this self-sustaining cascade reached a titer of (S)-3-hydroxy butyrate of 24 mM without requiring ATP and simultaneously recycling CoASH and NADH. This work illustrates the potential of in vitro biocatalysis to transform simple molecules into multi-functional ones.     

Site-Specific m6A Erasing via Conditionally Stabilized CRISPR-Cas13b Editor

N6-methyladenosine (m⁶A) on RNAs plays an important role in regulating various biological processes and CRIPSR technology has been employed for programmable m⁶A editing. However, the bulky size of CRISPR protein and constitutively expressed CRISPR/RNA editing enzymes can interfere with the native function of target RNAs and cells. Herein, we reported a conditional m⁶A editing platform (FKBP*-dCas13b-ALK) based on a ligand stabilized dCas13 editor. The inducible expression of this m⁶A editing system was achieved by adding or removing the Shield-1 molecule. We further demonstrated that the targeted recruitment of dCas13b-m⁶A eraser fusion protein and site-specific m⁶A erasing were achieved under the control of Shield-1. Moreover, the release and degradation of dCas13b fusion protein occurred faster than the restoration of m⁶A on the target RNAs after Shield-1 removal, which provides an ideal opportunity to study the m⁶A function with minimal steric interference from bulky dCas13b fusion protein.     

Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference**

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a K_D <20 μM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.     

四溴双酚A锑铝双金属化合物的合成及其阻燃性能

以四溴双酚Ａ（ＴＢＡ）合成了在水和空气中稳定的四溴双酚Ａ合锑铝双金属化合物（ＴＢＡＳＡ）．通过ＩＲ、１ＨＮＭＲ和元素分析予以表征，并研究了其对聚乙烯（ＰＥ）和聚环氧乙烷（ＰＥＯ）的阻燃性能．结果表明，这种分子中含有溴、锑和铝的化合物，对聚乙烯和聚环氧乙烷等高聚物材料有高的阻燃性能与消烟效果．     

On the Boussinesq/Full dispersion systems and Boussinesq/Boussinesq systems for internal waves

In this paper, we consider some asymptotic models for internal waves in the small amplitude/small amplitude regime, which were derived recently by Bona, Lannes and Saut. We first prove that the Boussinesq/Full dispersion systems and the Boussinesq/Boussinesq systems can be derived from the Full dispersion/Full dispersion systems. Then using a contraction-mapping argument and the energy method, we will prove that the derived systems that are linearly well-posed are in fact locally nonlinearly well-posed in suitable Sobolev classes. In particular, we improve and extend some known results on the well-posedness of Boussinesq systems for surface waves.