Science Pool

At Evotec we are committed to the development and usage of new technologies. With the objective to stay at the cutting edge of science and propose innovative solutions, several working groups have been created and are actively involved in various fields: photochemistry, electrochemistry, flow chemistry, biocatalysis... As part of this strategy, the working group “green chemistry” aims to design chemical products and processes that reduce or eliminate the use or generation of hazardous substances. We are always looking for safer, greener and cleaner methodologies to reduce the environmental impact of our activities and adopt the green chemistry principles¹. Green chemistry applies across the life cycle of a chemical product, including its design, manufacture, use, and disposal. Moreover, we are also engaged in energy saving to decrease the global carbon footprint of the company. Sustainability and green chemistry are implemented while maintaining our level of excellence in drug discovery. To reach our objectives, we have identified four areas of improvements:

This poster is focused on two areas in continuous improvement at Evotec: solvent alternatives and energy saving. Some examples of reactions carried out in renewable solvents such as MeTHF² and DMI³ are presented. Alternatives to DCM (potential ozone depletory and suspected carcinogenic solvent) usage for work-up and purification are also shown⁴.

The poster was presented by Kim Spielmann at the Journées de Chimie Organique held on 2-4 November 2022 at the École Polytechnique, Palaiseau, France.

¹Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, 30, By permission of Oxford University Press
² a) Coby J. Clarke, Wei-Chien Tu, Oliver Levers, Andreas Bröhl, and Jason P. Hallett Chemical Reviews 2018, 118, 747 b) Pace, V., Hoyos, P., Castoldi, L., Domínguez de María, P. and Alcántara, A.R. ChemSusChem 2012, 5, 1369 c) Andrew Jordan, Callum G. J. Hall, Lee R. Thorp, and Helen F. Sneddon Chemical Reviews 2022, 122, 6749
³ a) Aricò, F.; Tundo, P. Beilstein J. Org. Chem. 2016, 12, 2256 b) F. Aricò, A. S. Aldoshin, P. Tundo, ChemSusChem 2017, 10, 53 c) Russo F., Galiano F., Pedace F., Aricò F., and Figoli A. CS Sustainable Chem. Eng. 2020, 8, 1, 659
⁴ a) Peterson E.A., Dillon B., Raheem I., Richardson P., Richter D., Schmidte R. and Sneddon H.F. Green Chem., 2014,16, 4060 b) Taygerly J.P., Miller L.M., Yeec A. and Peterson E.A. Green Chem., 2012,14, 3020 c) MacMillan D.S., Murray J., Sneddon H.F., Jamiesona C. and Watson A.J.B. Green Chem., 2012,14, 3016

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As the CNS is a complex organ system, neurotoxicity can be difficult to assess and detect during preclinical development in animal models.

In this poster, we focus on:

• the use of cell-based models in conjunction with MEA to identify neurogenic and seizurogenic compounds
• a comparison between rat cortical neurons and a co-culture of human iPSC-derived glutamatergic neurons with iPSC-derived astrocytes in their response to known neurotoxic and seizurogenic compounds  
• a recommended in vitro screening approach for early detection of neurotoxicity

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During analysis of samples from HT-ADME screening, non-specific binding can cause challenges due to accumulation within the analytical system. This can result in poor peak shape, low sensitivity, increasing back pressure/pressure spikes, carryover or system clogging.  

In this poster, we focus on:

• the evaluation of the Waters^TM Acquity Premier UPLC in conjunction with the Acquity Premier HSS T3 column technology which contain an inert coating specifically formulated to eliminate analyte/surface interactions
• a comparison with standard UPLC technology
• details on the benefits of using the Waters Acquity^TM system in terms of chromatographic performance and sensitivity

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Cardiotoxicity in response to pharmaceutical drugs, chemicals and environmental toxicants can develop as a result of changes in structural integrity of cardiac tissue or functional changes in cardiac electrophysiology. The development of new approach methodologies (NAMs) is important in predicting these cardiotoxic liabilities.

In this poster, we focus on:

• the use of human iPSC-derived cardiomyocytes in combination with a panel of in vitro toxicology assays including:
  • calcium transient monitoring
  • high content imaging of morphological changes
  • cellular ATP assessment
  • high throughput transcriptomics using RNA-seq
• the results from profiling 42 compounds in the assessment of structural and functional endpoints along with predictive outcome (sensitivity, specificity and accuracy)
• mechanistic information including the detection of biological pathways associated with the cardiotoxic effects

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The cytochrome P450 enzyme, CYP46A1, is predominantly expressed in the brain and plays a major role in cholesterol metabolism by converting cholesterol to 24-hydroxy cholesterol.

In this poster, we focus on:

• the development and validation of an in vitro high throughput screening platform for characterisation of inhibitors and activators of CYP46A1
• a comparison of testosterone with cholesterol as a potential replacement probe substrate for studying CYP46A1 metabolism
• data generated from a screening cascade of 2321 FDA approved drugs

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The tuberculosis lesion environment is highly complex. Mycobacterium tuberculosis (M.tb) reside in various niches and their metabolism and other characteristics, including drug tolerance depend on the specific environmental characteristics of those niches. So-called persister bacteria refer to those that are difficult to eradicate with drug treatment and that may contribute to the long durations of TB treatment required for cure. Many in vitro models have been developed in attempts to mimic these niches with the objective of determining potential anti-TB compound activity in models that reflect M.tb’s characteristics in vivo.
Foamy macrophages Foam-M are characterized by lipid body accumulation induced by Mtb infection and they may be an important niche for Mtb during infection.

In this poster we:

• We describe the development of a robust 96 well plate Foamy macrophages assay designed to mimic this niche, and suitable for medium-high throughput evaluation of compound activity during drug discovery.
• We describe TB compounds activity in the foamy macrophage assay compared to other TB current assays
• We show that infection of foamy macrophage does not trigger an anti-inflammatory response in host cells

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Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). It is still a major public health problem with 250 million chronically HBV-infected patients worldwide with none of the current treatments leading to a cure.
More effective treatments are needed to achieve HBV cure in a large proportion of patients.
We aim to develop a treatment, combining simultaneous stimulation of CD40 and IFN-I pathway, which leads to a strong anti-HBV effect with minimal inflammation.

In this poster we:

• Present the key results that demonstrated the potential of such combination to induce anti-HBV effects in vitro and in vivo
• Introduce the design of our new antibody-based therapeutic that combine the two modalities in one single molecule
• Demonstrate the efficacy of the molecule in HBV infection system in Primary Human Hepatocytes
• Show key results from our preclinical safety assessment in vitro and in vivo in Non-Human Primate

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Full poster title: Development of recombinase-based targeted integration systems for production of exogenous proteins using transposon-mediated landing pads

Summary of the poster:

• We demonstrated proof of principle of targeted integration systems in our CHO host cell line with consistent genome integration into expected landing pad sites
• Test cases using three antibody or antibody-fusion therapeutic molecules showed similar levels of productivity
• We also show preliminary data from ongoing work to build upon these targeted integration systems, which includes isolating a single-copy landing pad cell line and developing a CHO display platform

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In this poster, presented at SfN 2018, Sessolo et al. present 3Brain high-density multi electrode array (HD-MEA) as a system to monitor and characterize seizure-like activity in hippo-cortical slices induced by different compounds.

The high system resolution allows to monitor in detail the entire slice and through the software showing the activity map (in real-time) the sign of compounds' action is easily found.

The technology allows to acquire Local Field Potential (LFP), Multi Unit Activity (MUA) and Single-Unit Activity.

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This poster includes information about:

• Functional brain slice electrophysiology by HD-MEA platform
• Combined neuronal circuitry studies through functional brain tissue imaging

Initially presented at FENS 2018 by Ugolini et al., 3Brain high-density multi electrode array (HD-MEA) as a system for long lasting monitor and characterize spiking activity of hundreds Purkinje cells simultaneously by using different positive and negative Ca++-activated K+ channels. Responses can be evaluated though different analysis. It is a useful tool for compounds validation on cerebellar slices.

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