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NP Navigator: A New Look at the Natural Product Chemical Space.
No full textNatural products (NPs), being evolutionary selected over millions of years to bind to biological macromolecules, remained an important source of inspiration for medicinal chemists even after the advent of efficient drug discovery technologies such as combinatorial chemistry and high-throughput screening. Thus, there is a strong demand for efficient and user-friendly computational tools that allow to analyze large libraries of NPs. In this context, we introduce NP Navigator - a freely available intuitive online tool for visualization and navigation through the chemical space of NPs and NP-like molecules. It is based on the hierarchical ensemble of generative topographic maps, featuring NPs from the COlleCtion of Open NatUral producTs (COCONUT), bioactive compounds from ChEMBL and commercially available molecules from ZINC. NP Navigator allows to efficiently analyze different aspects of NPs - chemotype distribution, physicochemical properties, biological activity and commercial availability of NPs. The latter concerns not only purchasable NPs but also their close analogs that can be considered as synthetic mimetics of NPs or pseudo-NPs
The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Phenotypic Drug Discovery
No full textPhenotypic Drug Discovery has a long track record of delivering innovative drugs and has received renewed attention in the last few years. The promise of this approach, however, comes with several challenges which should be addressed to avoid wasting time and resources on drugs with undesired modes of action or, worse, false positive hits. In this set of best practices, we go over the essential steps of phenotypic drug discovery and provide guidance on how to increase the chance of success of identifying validated and relevant chemical starting points for optimization: selecting the right assay, selecting the right compound screening library and developing appropriate hit validation assays. Then, we highlight the importance of initiating studies to determine the mode of action of the identified hits early and present the current state-of-the-art
The pharmacology of the prostaglandin D2 receptor 2 (DP2) receptor antagonist, fevipiprant
No full textFevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the prostaglandin D2 (DP2) receptor. The DP2 receptor is a mediator of inflammation expressed on the membrane of key inflammatory cells, including eosinophils, Th2 cells, type 2 innate lymphoid cells, CD8+ cytotoxic T cells, basophils and monocytes, as well as airway smooth muscle and epithelial cells. The DP2 receptor pathway regulates the allergic and non-allergic asthma inflammatory cascade and is activated by the binding of prostaglandin D2. Fevipiprant is metabolised by several uridine 5′-diphospho glucuronosyltransferase enzymes to an inactive acyl-glucuronide (AG) metabolite, the only major human metabolite. Both fevipiprant and its AG metabolite are eliminated by urinary excretion; fevipiprant is also possibly cleared by biliary excretion. These parallel elimination pathways suggested a low risk of major drug-drug interactions (DDI), pharmacogenetic or ethnic variability for fevipiprant, which was supported by DDI and clinical studies of fevipiprant. Phase II clinical trials of fevipiprant showed reduction in sputum eosinophilia, as well as improvement in lung function, symptoms and quality of life in patients with asthma. While fevipiprant reached the most advanced state of development to date of an oral DP2 receptor antagonist in a worldwide Phase III clinical trial programme, the demonstrated efficacy did not support further clinical development in asthma
Tablet formulation development focusing on the functional behaviour of water uptake and swelling
No full textThe functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of
excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active
pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are
typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of
a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of
tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The
impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the
analysis results for Eudragit L100–55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and
swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the
addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The
application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an
empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of
varying tablet formulations and structural properties
Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38
No full textWhile molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for each of the different cell types. In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints – mechanisms that restrict cell cycle progression of cells that are smaller than their target size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cell’s actual size and its target size. In the present study, we materialize this distinction by describing experimental assays that discriminately quantify the target size value of cells. With these assays, we show that a cell’s size and target size are distinct phenotypes that are dictated by different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cell’s target size value is regulated by other pathways including CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, it does not change the target size that is required for the G1/S transition. The CDK4-cyclinD1/Rb pathway has previously been proposed to regulate target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size have not been validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to dial higher and lower levels of CDK4 activity. These measurements identified roles of CDK4 on target size determination that are distinct from other G1 CDKs. CDK4 activity shifts the target size threshold below which inappropriately small cells exhibit elevated p38 activity. Using C. elegans, we show that these influences of CDK4 on size determination also function in vivo. Our data support a model where mTORC1, p38, and CDK4 cooperate in a manner analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostat dial that sets the critical target size associated with cell size homeostasis
Safe Scale-Up of a NBS-Involved Bromination Reaction: Thermal Safety Analysis Contributes to Process Optimization
No full textA hazardous side reaction between N-bromosuccinimide (NBS) and 2-methyltetrahydrofuran (2-MeTHF) was identified during the thermal safety analysis towards a bromination process. The thermal behaviors of the side reaction was investigated by Calvet calorimeter C80 in a membrane mixing cell. A delay to initiate the reaction was observed, and it was owing to a preferred free-radical mechanism that the reaction could follow. The Advanced Kinetics and Technology Solutions (AKTS) software was used to study the thermo-kinetics of the side reaction, and its reaction progress under the proposed process temperature was predicted. The influence of NBS concentration on the side reaction was studied by differential scanning calorimeter (DSC). It was proved that the maximum reaction heat could be lowered by limiting the accumulation of NBS in the reaction mixture. Besides, the heat flow of the process desired reaction was simulated by reaction calorimeter (RC1), indicating the bromination could be controlled under a semi-batch mode with appropriate feeding program of NBS. On the basis of the investigation, two batches bromination process with 106 kg starting material were safely scaled up in pilot plant with expected yield
Simultaneous machine-directed evolution of an imine reductase for activity and stereoselectivity
No full textBiocatalysis is an effective tool to access small quantities of chiral molecules that are otherwise hard to synthesize or purify. A time-efficient process is needed to develop an enzyme that is adequate to perform desired chemistry. We evaluated machine-directed evolution as an enzyme engineering strategy, using a stereoselective imine reductase as the model system. Within one cycle, it was found that machine-directed evolution yielded a library of high activity mutants with a dramatically shifted activity distribution, compared to traditional directed evolution. Structure-guided analysis revealed that linear additivity may provide a simple explanation for the effectiveness of machine-directed evolution. The study concludes with a cost-benefit analysis showing that machine-directed evolution gives a good return on investment in high cost per measurement regimes
WDII Unpacking and Startup Video
No full textAbstract N/A. This video will be shared with prospective and current customers to acquaint them with the device as well as assist in DIY setup of the device once delivered
Decade-long Remissions of Leukemia Sustained by the Persistence of Activated CD4 CAR T Cells
No full textThe adoptive transfer of T cells reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term memory potential and the clonal stability of the infused cells. Here, we studied the fate of CD19 redirected chimeric antigen receptor (CAR19) T-cells in two leukemia patients who achieved and sustained a complete remission almost a decade ago. CAR T cells were still detectable 9+ years post-infusion. Surprisingly, a prominent, highly activated CD4+ population developed in both subjects in the years post-infusion, dominating the CAR T cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by few clones. Single-cell profiling of CAR T-cells obtained 9 years post-infusion demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Given data that CD19 directed CAR T with a CD28 signaling domain do not persist long term, our data provide important insight into the development of long-term anti-tumor responses necessary for sustained remission in leukemia following CAR T-cell therapy
Inhibitive S. aureus Infection to HUVECs Induced by Trehalose and Glucose-functionalized Gold Nanoparticles
No full textMicrobial adhesion to host cells represents the initial step in the infection process. Several methods have been explored to inhibit microbial adhesion including the use of glycopolymers based on mannose, galactose, sialic acid and glucose. These sugar receptors are however abundant in the body and they are not unique to bacteria. Trehalose in con-trast is a unique disaccharide that wildly expressed by mi-crobes. The role of trehalose in bacteria has widely been in-vestigated but this carbohydrate has not yet been explored as anti-adhesive. Herein, gold nanoparticles (AuNPs) coated with trehalose-based polymers have been prepared and compared to AuNPs coated with glucose-functionalized were developed to inhibit. Acting as anti-adhesive, trehalose-functionalized nanoparticles particularly decreased the infec-tion of HUVEC cells by S. aureus, while outperforming the control nanoparticles. Microscopy revealed that trehalose coated nanoparticle bind strongly to S. aureus compared to the controls. As a conclusion, nanoparticles based on treha-lose could be suitable to inhibit S. aureus infection