Science Pool

Download this whitepaper to learn more about our integrated approach to drug abuse liability assessment including:

• The impact of scheduling
• Animal behavioural studies
• Human abuse liability studies

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Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19.

Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories.

• In this paper we describe strategies used to prioritize thousands of β-lactams from multiple companies into a small test set for further characterization.
• In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor.
• One potent cephaloporin was active in Mtb-infected mice.

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The 12^th edition of our Drug Discovery Update (DDup) provides insights into exciting new developments in 3D cell models including microtissues, organoids and organ-on-a-chip technology.

In this edition, it covers:

• an introduction to 3D cellular models
  • the need for better models to improve translation from in vitro to in vivo
  • the relevance of 3D cellular models to kidney disease modelling and drug induced toxicity prediction
• an overview of Evotec's 3D in vitro platforms
  • glomerulus-on-a-chip to study kidney disease
  • kidney organoids to study polycystic kidney disease
  • organ microtissues to predict drug-induced toxicity
• interviews with experts Dr Christodoulos Xinaris, Dr Reiner Class, Dr Magali Ferro and Dr Stephanie Ryder

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Huntington´s Disease (HD) is a hereditary neurodegenerative disorder that is caused by a mutation in the huntingtin gene (mHTT) leading to deposition of pathologic protein aggregates in the brain.

This paper focuses on:

• Visualization of mHTT aggregate expression by positron emission tomography (PET) in rodent HD model
• Utility of the previously described novel PET imaging ligand CHDI-180 for detection of mHTT in rodent and post-mortem human HD brain
• Ability of CHDI-180 to serve as functional response indicator for mHTT lowering therapies

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Learn more about fighting tuberculosis by targeting the essential enzyme PptT.

Together with collaborators at Weill Cornell Medical College, Texas Agricultural and Mechanical University (TAMU), and  University of North Carolina (UNC), we identified the amidinourea compound AU8918, through a phenotypic screen, as an interesting anti-TB compound. We went on to identify its target within Mycobacterium tuberculosis, as phosphopantetheinyl transferase (PptT) - an essential enzyme involved in synthesis of cellular lipids and virulence factors.

This paper describes:

• Next steps taken in further pursuit of this novel anti-TB series
• An expanded collaboration within the TB Drug Accelerator consortium
• Latest structure guided SAR exploration around AU8918 for more potent and safest Lead-like analogs

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SARM1 is a NADase whose action triggers the destruction of axons and development of novel SARM1 inhibitors which enables the prevention or delay of neurodegenerative disorders. This paper identifies the binding site for the SARM1 agonist NMN and reveals the structure of full-length SARM1 as elucidated by cryo-electron microscopy (cryo-EM). The structure of apo SARM1 was revealed as an octameric ring, held in an autoinhibitory state by the separation of the active TIR domain at the rim of the ring. The elucidation of autoinhibition release and the identification of the NMN binding site within the autoinhibitory ARM domain opens a path to inhibition of SARM1 via stabilisation of its inactive form. These studies were possible through the close co-ordination of the new cryo-EM team at Evotec, Abingdon with Disarm and academic collaborators in Australia and the USA.

Proposed SARM1 activation mechanism:

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Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence.

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Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). In this recent article, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus

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Over recent years, interest in the multi-attribute method (MAM) has grown and the technique has become an important mass spectrometry-based tool for identifying and quantifying the site-specific product attributes and purity information for biotherapeutics such as monoclonal antibodies (mAbs) and fusion molecules. Improving the throughput of sample preparation without introducing chemical modifications and variability will further increase the utility of MAM in drug development.

In this publication, we focus on:

• the development of a fully automated MAM sample preparation protocol incorporating rapid desalting (< 15 min) using miniaturized size-exclusion chromatography columns in pipette tips on an automated liquid handling system which leads to complete rapid digestion of mAbs in approximately 3 hours with excellent reproducibility
• analysis of samples using electrospray ionization mass spectrometry coupled to a U-HPLC system with dual column switching 
• comparison of the new sample preparation method versus manual low artefact sample preparation including analysis of reproducibility, recovery, efficiency and flexibility

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The 11^th edition of our Drug Discovery Update (DDup) is dedicated to biotherapeutics discovery and development with a focus on artificial intelligence and machine learning and its opportunity in transforming antibody discovery.

In this edition, it covers:

• an introduction to antibodies including:
  • an overview of monoclonal antibodies as therapeutic agents
  • a history of antibody drug discovery platforms
• how Just - Evotec Biologics are exploiting artificial intelligence and machine learning to generate a novel humanoid antibody library biased towards highly desirable features
• a description of the process from idea to IND and beyond for antibody discovery and development
• facts and figures on the market for therapeutic antibodies
• an overview of function-focused antibody (FFmab) screening
• an interviews with the experts

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