Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL^pro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL^pro. Moreover, we report the discovery of isoindolines as a new class of potent PL^pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL^pro are valuable starting points for the development of new pan-coronaviral inhibitors.     

Malic acid production from renewables: a review

Malic acid derived from fossil resources is currently applied in the food and beverage industries with a medium global production capacity. However, in the transition from a fossil-based to a bio-based economy, biotechnologically produced l -malic acid may become an important platform chemical with many new applications, especially in the field of biopolymers. In this review, currently used petrochemical production routes to dl -malic acid are outlined and insights into possible bio-based alternatives for microbial l -malic acid production are provided. Besides ecological reasons, the possibility to produce enantiopure l -malic acid by microbial fermentation is the biggest advantage over chemical synthesis. State-of-the-art and open challenges concerning production host engineering, substrate choice and downstream processing are addressed. With regard to production hosts, a literature overview is given covering the leading natural production strains of Aspergillus, Ustilago and Aureobasidium, as well as Escherichia coli as the most important engineered recombinant host. The utilization of renewable substrates as an alternative to glucose is emphasized in particular as a key aspect for a competitive bio-based production. Out of the alternative substrates discussed in this review, the industrial side-streams crude glycerol and molasses seem to be most promising for large-scale l -malic acid production. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.     

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGlo^TM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.     

Aliasing and adversarial robust generalization of CNNs

Many commonly well-performing convolutional neural network models have shown to be susceptible to input data perturbations, indicating a low model robustness. To reveal model weaknesses, adversarial attacks are specifically optimized to generate small, barely perceivable image perturbations that flip the model prediction. Robustness against attacks can be gained by using adversarial examples during training, which in most cases reduces the measurable model attackability. Unfortunately, this technique can lead to robust overfitting, which results in non-robust models. In this paper, we analyze adversarially trained, robust models in the context of a specific network operation, the downsampling layer, and provide evidence that robust models have learned to downsample more accurately and suffer significantly less from downsampling artifacts, aka. aliasing, than baseline models. In the case of robust overfitting, we observe a strong increase in aliasing and propose a novel early stopping approach based on the measurement of aliasing.

     

Sterol and fatty acid composition of neutral lipids ofParatenuisentis ambiguus and its host eel

The sterol composition of free sterol and steryl ester fractions of the fish parasiteParatenuisentis ambiguus was determined. In addition, the fatty acid composition of various neutral lipid classes, i.e., wax esters, steryl esters, triacylglycerols and free fatty acids, as well as the composition of the 1-O-alkyl moieties of total ether glycerolipids of the parasite, were investigated. The results of these studies were compared with those obtained on the intestinal tract tissue of its host, the eel (Anguilla anguilla). Cholesterol is the major sterol in bothP. ambiguus andA. anguilla. However, the sterols ofP. ambiguus contain high proportions (>20%) of other sterols, such as campesterol and various dehydrosterols. [e.g., 7-dehydrocholesterol and cholesta-5,22(E)-dienol]. The presence of these minor sterols agrees with the known biotransformations of exogenous sterols in various helminths. Considerable differences are found in the fatty acid composition of neutral lipid fractions, as well as the total lipid extract from the endoparasite as compared to the host tissue. In particular, eicosapentaenoic acid (20∶5n−3), other polyunsaturated fatty acids, such as 20∶4n−6, 22∶5n−3 and 22∶6n−3, as well as long-chain saturated fatty acids, such as 20∶0, are generally enriched in the neutral lipid fractions of the parasite as compared to those of infected eel intestine. The analysis of ether glycerolipids revealed that 1-O-hexadecyl (16∶0) and 1-O-hexadecenyl (16∶1) moieties were present in similar proportions in the ether lipids of bothP. ambiguus and eel intestine, whereas 1-O-octadecyl (18∶0) moieties are more prominent in the parasite and 1-O-octadecenyl (18∶1) moieties in the eel. The results of these studies show thatP. ambiguus has specific mechanisms for the regulation of the sterol and fatty acid composition of its neutral lipids. Dedicated to Professor Helmut K. Mangold on the occasion of his 70th birthday.     

Two Subtle Amino Acid Changes in a Transaminase Substantially Enhance or Invert Enantiopreference in Cascade Syntheses

Amine transaminases (ATAs) are powerful enzymes for the stereospecific production of chiral amines. However, the synthesis of amines incorporating more than one stereocenter is still a challenge. We developed a cascade synthesis to access optically active 3‐alkyl‐substituted chiral amines by combining two asymmetric synthesis steps catalyzed by an enoate reductase and ATAs. The ATA wild type from Vibrio fluvialis showed only modest enantioselectivity (14 % de) in the amination of (S)‐3‐methylcyclohexanone, the product of the enoate‐reductase‐catalyzed reaction step. However, by protein engineering we created two variants with substantially improved diastereoselectivities: variant Leu56Val exhibited a higher R selectivity (66 % de) whereas the Leu56Ile substitution caused a switch in enantiopreference to furnish the S‐configured diastereomer (70 % de). Addition of 30 % DMSO further improved the selectivity and facilitated the synthesis of (1R,3S)‐1‐amino‐3‐methylcyclohexane with 89 % de at 87 % conversion.     

Design,Synthesis and Biological Evaluation of Highly Potent Simplified Archazolids

The archazolids are potent antiproliferative compounds that have recently emerged as a novel class of promising anticancer agents. Their complex macrolide structures and scarce natural supply make the development of more readily available analogues highly important. Herein, we report the design, synthesis and biological evaluation of four simplified and partially saturated archazolid derivatives. We also reveal important structure-activity relationship data as well as insights into the pharmacophore of these complex polyketides.     

Herausforderungen und Chancen für die Arbeit der Akademie für Ethik in der Medizin angesichts der COVID-19-Pandemie

Ethik in der Medizin -     

Evaluating semantometrics from computer science publications

Scientometrics - Identification of important works and assessment of importance of publications in vast scientific corpora are challenging yet common tasks subjected by many research projects....