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Structure Determination of Terpenes by The Crystalline Sponge Method
No full textThe crystalline sponge method was used to produce novel encapsulation complexes with the aim of structural determination of terpenes, such as geraniol-monoterpenoid, farnesol-sesquiterpenoid and β-damascone-tetraterpenoids. Along with the structure determination of the terpenoids, non-bonding CH-π, π-π interactions were identified in the host-guest complexes, which were responsible for holding the guests in the specific position with respect to the framework. In addition, the geometry of guests with respect to the framework was studied
The discovery of SWI/SNF chromatin remodeling activity as a novel and targetable dependency in uveal melanoma
No full textUveal melanoma is a rare and aggressive cancer that originates in the uveal tissue of the eye. Currently, there are no approved targeted therapies for this cancer, and very few effective treatments are available. While activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, other targetable molecular players are only partially understood. Through new analysis of unbiased, functional genomics screens and comprehensive validation studies in a panel of uveal melanoma cell lines, we find evidence that the SWI/SNF complex is essential in uveal melanoma. The mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) are often mutated in cancers and described as tumor suppressors, yet context specific roles for these complexes in the maintenance of certain cancers are beginning to emerge. We determined that the catalytic activity of SWI/SNF is critical, and further translated these findings with our recently described small molecule inhibitors of BRM and BRG1, the closely related catalytic subunits of the SWI/SNF complexes. Finally, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage specific transcription factor MITF, suggesting that SWI/SNF cooperates with MITF to drive a lineage specific transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path to the treatment of this cancer
Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO)
No full textMyeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective 6-substituted indoles with good oral bioavailability and in vivo activity
Screening medications for association with progression to wet age-related macular degeneration (AMD)
No full textThere is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to wet AMD. If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses while adjusting for multiple testing, to screen for associations between drugs and delayed progression to wet AMD
Nonclinical safety assessment of an inhaled formulation of serelaxin, a recombinant human protein, in rats and cynomolgus monkeys (Macaca fascicularis)
No full textSerelaxin is a recombinant human relaxin-2 intended for cardiovascular indications. Inhalation was chosen as alternative route to IV to allow daily administration for chronic applications and home treatment. A total of 4 short-term studies were conducted in rats and cynomolgus monkeys with inhaled formulation of serelaxin at dose up to 10 mg/kg/day. All rats and cynomolgus macaques receiving serelaxin were exposed to the test item. One rat and approximately 50% of macaques developed immunogenicity, which did not appear to affect exposure. No adverse effect on respiratory function or systemic changes were noted. Both species developed similar microscopic lesions characterized by eosinophilic cell infiltration around bronchi, however in the rat, this was more pronounced and extended to a perivascular location. In addition, in the rat, serelaxin showed eosinophilic crystalline material associated with macrophages in the alveoli and bronchioles. In macaques, serelaxin induced minimal macrophage infiltrates in alveoli and perivascular/peribronchiolar mononuclear cell infiltrations. The minimal airway eosinophilic/mononuclear inflammatory cell infiltrations were considered to be non-adverse in macaques due to the minimal severity and the lack of any other alterations in the lung parenchyma. In the rat, the presence of eosinophilic crystalline material and macrophage response, characterized as precipitated test article, was considered advers
A general kilogram scale protocol for Suzuki-Miyaura cross-coupling in water with TPGS-750-M surfactant
No full textThe development of a kilogram scale protocol for a Suzuki–Miyaura cross-coupling step toward the synthesis of the drug candidate LSZ102 is described. Particularly, the use of the surfactant TPGS-750-M in water as a medium for the transformation and its impact on the selectivity and quality are reported. Minimization of typical impurities generated during the cross-coupling (e.g., dehalogenation) has been in focus during our study. The environmental and cost impacts using such a process are also discussed
Rational design to biologics development: The polysorbates point of view
No full textFormulation development is an essential part of any biopharmaceuticals development programme, and this will affect quality, safety and efficacy of the final drug product. The vast majority of biopharmaceuticals on the market are therapeutic proteins; however, these are less stable compared to conventional pharmaceuticals. To counter aggregation, denaturation and surface adsorption of proteins in solution, surfactants are added to the formulations; however, the choice of the best formulation is a challenge that is faced during formulation development. Polysorbates are the most widely used surfactants in the pharmaceutical industry and are presented in >80% of commercial monoclonal antibody formulations. In this review, we provide a general overview of polysorbates and their issues, and the characteristics that have to be taken into account during formulation development. Degradation of polysorbates, namely by hydrolysis and/or oxidation, is one of the main concerns associated with their use. Furthermore, degradation of polysorbates is determined by formulation composition, pH and storage conditions, therefore underlining the importance and complexity of protein formulation development using polysorbates. A need-based approach should be used for correct selection of excipients in protein formulations that contain polysorbates
Cell types of the human retina and its organoids at single-cell resolution: developmental convergence, transcriptomic identity, and disease map
No full textHow closely human organoids recapitulate cell-type diversity and cell-type maturation of their target organs is not well understood. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers. We sequenced the RNA of 158,844 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable ‘developed’ state at a rate similar to human retina development in vivo and the transcriptomes of organoid cell types converged towards the transcriptomes of adult peripheral retinal cell types. The expression of disease-associated genes was significantly cell-type specific in adult retina and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas
Multimodal small-molecule screening for human prion protein binders
No full textPrion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by stabilizing the native protein or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Additional orthogonal approaches to PrP binder discovery should be pursued in parallel with non-small-molecule modalitie
Targeted Locus Amplification and NGS combined with qPCR-based breakpoint analysis for the assurance of monoclonality in recombinant cell lines
No full textRecombinant protein therapeutics are routinely produced in Chinese hamster ovary (CHO) cells. Minimizing the heterogeneity within a Master Cell Bank (MCB) allows for a well-controlled process that is capable of the consistent manufacture of a product. Regulatory authorities therefore expect that clonal CHO cell lines are used. In this paper, we describe a rapid, reliable and cost-effective assessment of the probability of clonal derivation of recombinant cell populations by combining TLA and NGS with MCB-specific breakpoint qPCR assays and statistical analyses