Science Pool

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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N-Methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has been recently identified as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy.

Identification of a new hit for GluN2A PAMs is however difficult due to the similarity of PAM binding sites between GluN2A and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs), another member of the ionotropic glutamate receptor family.

In this collaborative publication with Takeda, we focus on:

• Identification of an hit compound with moderate AMPAR-binding activity, though a Ca²⁺ influx-based high throughput screening campaign with a compound set including an internal AMPAR-focused compound library
• The strategy using a structure-based drug design (SBDD) approach to minimize the AMPAR-binding activity while improving GluN2A activity
• The use of the potent and brain-penetrable GluN2A-selective positive allosteric modulators GluN2A PAM discovered as in vivo tool exhibiting significant neuroplastic enhancement in the rat hippocampus 24h after oral administration, having potential application for cognitive enhancement in neuropsychiatric diseases

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Pneumonia induced by multidrug resistant (MDR) Acinetobacter baumannii strains is among the most common and deadly forms of healthcare acquired infections. Animal models play a critical role during the preclinical assessment of novel therapeutic approaches, however, only a self-limiting pneumonia with no or limited local bacterial replication is frequently obtained when MDR A. baumannii is the pathogen.

To strengthen and characterise a sustained lung infection model, in this publication, we focus on:

• the ability of intranasal inoculation, intratracheal instillation and oropharyngeal aspiration methods of administration of the bacterial challenge to induce a robust pneumonia in mice
• the characterisation of the infection model obtained after intratracheal instillation and oropharyngeal aspiration in terms of histopathological examination of pulmonary lesions, biomarkers of inflammation and leukocytes cells infiltration after treatment with either vehicle or with the antibiotic tigecycline efficacious into reducing lung bacterial load.

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This article published in Nature describes a first-in-class METTL3 inhibitor for the treatment of acute Myeloid Leukaemia.

The publication covers:

• Development of STM2457 following high-throughput screen
• Selectivity screening across the panel of 45 human methyltransferases
• Crystal structure of METTL3-14 complex with STM2457, part of structure-based drug design strategy for this target
• Compound validation in cellular assays and in vivo efficacy

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Stable expression of recombinant protein therapeutics in CHO cells often relies on random or semi-random genomic integration events which results in a widely heterogenous cell population. This leads to significant effort in clone screening during cell line development in order to identify clones with high expression, growth and product quality. 

In this publication, we focus on:

• the development of two targeted integration systems that express high levels of recombinant protein in CHO cells by: 
  • the installation of rationally designed piggyBac-based chromosomal landing pads
  • the use of site specific recombinases including PhiC31 and CRE 
• demonstration of the functional integration of several donor vectors encoding various therapeutic proteins including two monoclonal antibodies and one Fc-fusion molecule

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In this article, we discuss the role of structure-based virtual screening in drug discovery. 

The publication covers:

• an overview of structural-based virtual screening and the importance of selecting the most appropriate protocol for affinity estimation calculations
• the development of an automated calibration process implemented in a Knime workflow consisting of 4 steps:
  • preparation of a protein test set with structures and models of the target
  • preparation of a compound test set with target-related ligands and decoys
  • automatic test of 24 scoring/rescoring protocols for each target structure and model
  • graphical display of the results
•  demonstration of the application of this tool in setting up an optimal protocol for structure-based virtual screening against Retinoid X Receptor alpha

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This article forms a book chapter in Quantum Mechanics In Drug Discovery which is part of the Methods in Molecular Biology book series.

In this article, we discuss the use of quantum mechanics in understanding receptor-ligand interactions and chemical reactions.

The chapter includes:

• an overview of the use of quantum mechanics methods in drug design and drug discovery
• presentation of the most popular quantum mechanics methods and software packages
• discussion of recent representative applications in drug design and drug discovery

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