The evolving role of investigative toxicology in the pharmaceutical industry

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(4), P. 317 - 335

Published: Feb. 13, 2023

For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects were carefully reported and used as basis to calculate safety margins for drug candidates. In recent years, however, technological advances have increasingly enabled researchers gain insights into toxicity mechanisms, supporting greater understanding of species relevance translatability humans, prediction events, mitigation side development biomarkers. Consequently, investigative (or mechanistic) has been gaining momentum is now key capability the pharmaceutical industry. Here, we provide an overview current status field using case studies discuss potential impact ongoing developments, based on survey toxicologists from 14 European-based medium-sized large companies. Investigative tools strategies are companies reduce safety-related attrition development. This Perspective article summarizes goals toxicology, highlights approaches discusses selected emerging technologies that improve safety-testing paradigm.

Language: Английский

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Reviewing the Significance of Blood–Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 8370 - 8370

Published: Aug. 4, 2021

The disruption of blood-brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset immune attack and later CNS self-sustained 'inside-out' demyelination neurodegeneration processes. This review presents characteristics BBB malfunction in MS but mostly highlights current developments regarding impairment neurovascular unit (NVU) metabolic mitochondrial dysfunctions BBB's endothelial cells. hypoxic hypothesis is largely studied agreed upon recently pathologic processes MS. Hypoxia might be produced per se by NVU or secondary to mitochondria dysfunction. We present three different related terms that denominate ongoing neurodegenerative process progressive forms are indirectly disruption: progression independent relapses, no evidence disease activity smoldering silent progression. Dimethyl fumarate (DMF), modulators S1P receptor, cladribine laquinimode DMTs able cross exhibit beneficial direct effects with very mechanisms action, providing hope combined therapy effective treating Detailed action these described also illustrated dedicated images. With increasing knowledge about involvement pathology, become therapeutic target not only make it impenetrable against activated cells allow molecules have neuroprotective effect reaching cell inside CNS.

Language: Английский

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GPCR drug discovery: new agents, targets and indications

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

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Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism

Nature Chemical Biology, Journal Year: 2021, Volume and Issue: 18(3), P. 281 - 288

Published: Dec. 22, 2021

Language: Английский

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An Overview of the History, Pathophysiology, and Pharmacological Interventions of Multiple Sclerosis

Cureus, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 2, 2023

Multiple sclerosis (MS) is an immune-inflammatory disease that attacks and damages myelinated axons in the central nervous system (CNS) causes nontraumatic neurological impairment young people. Historically, Lidwina of Schiedam documented first MS case. After that, Augustus d'Este wrote for years about how his symptoms worsened. Age, sex, genetics, environment, smoking, injuries, infections, including herpes simplex rabies, are risk factors MS. According to epidemiology, average age onset between 20 40 years. more prevalent women common Europe America. As diagnostic methods criteria change, people with may be discovered at earlier stages disease. therapy has advanced dramatically due breakthroughs our knowledge disease's etiology progression. Therefore, efficacy treatment medications increased exponentially. Management goals include reducing lesion activity avoiding secondary Current approaches focus on managing acute episodes, relieving symptoms, biological activity. Disease-modifying drugs such as fingolimod, interferon-beta, natalizumab, dimethyl fumarate most widely used treatments For proof safety these medications, investigations real world necessary.

Language: Английский

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Central nervous system demyelinating diseases: glial cells at the hub of pathology

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 16, 2023

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is most frequent studied, as it affects about a million people USA alone. The understanding mechanisms underlying their pathology has been advancing, although there still no highly effective disease-modifying treatments for progressive symptoms disability late stages disease. Among these mechanisms, action glial cells upon lesion regeneration become prominent research topic, helped not only by discovery glia targets autoantibodies, but also role on CNS homeostasis neuroinflammation. In present article, we discuss participation IDDs, well association with demyelination synaptic dysfunction throughout course disease experimental models, focus MS phenotypes. Further, involvement microglia astrocytes formation organization, remyelination, induction pruning through different signaling pathways. We argue that evidence several glia-mediated supports viable therapy development.

Language: Английский

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Immune System Dysregulation in the Progression of Multiple Sclerosis: Molecular Insights and Therapeutic Implications

Neuroscience, Journal Year: 2024, Volume and Issue: 548, P. 9 - 26

Published: April 30, 2024

Language: Английский

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Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3585 - 3585

Published: April 10, 2025

Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to pathogenesis autoimmune demyelinating diseases such as multiple sclerosis neuromyelitis optica spectrum disorder. This review explores origins microglia macrophages, well their mechanisms activation, interactions with other neural cells, contributions disease progression repair processes. It also highlights translational relevance insights gained animal models therapeutic potential targeting microglial macrophage activity

Language: Английский

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A Review of Biologically Active Oxime Ethers

Molecules, Journal Year: 2023, Volume and Issue: 28(13), P. 5041 - 5041

Published: June 28, 2023

Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence this moiety affects biological activity compounds. In review, structures oxime with specific have been collected and presented, bactericidal, fungicidal, antidepressant, anticancer herbicidal activities, among others, described. review includes both those substances that currently used as drugs (e.g., fluvoxamine, mayzent, ridogrel, oxiconazole), well non-drug for which various studies conducted. To best our knowledge, is first such authors hope will inspire scientists to take greater interest in group compounds, it constitutes an interesting research area.

Language: Английский

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Fine-tuning activation specificity of G-protein-coupled receptors via automated path searching

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(8)

Published: Feb. 12, 2024

Physics-based simulation methods can grant atomistic insights into the molecular origin of function biomolecules. However, potential such approaches has been hindered by their low efficiency, including in design selective agonists where simulations myriad protein–ligand combinations are necessary. Here, we describe an automated input-free path searching protocol that offers (within 14 d using Graphics Processing Unit servers) a minimum free energy (MFEP) defined high-dimension configurational space for activating sphingosine-1-phosphate receptors (S1PRs) arbitrary ligands. The distributions along MFEP four distinct ligands and three S1PRs reached remarkable agreement with Bioluminescence Resonance Energy Transfer (BRET) measurements G-protein dissociation. In particular, revealed transition state structures pointed out toward two S1PR3 residues F263/I284, dictate preference existing CBP307 BAF312 on S1PR1/5. Swapping these between S1PR1 reversed response to BRET assays. These results inspired us improved both strong polar head bulky hydrophobic tail higher selectivity S1PR1. Through merely silico iterations, our tool predicted unique compound scaffold. assays confirmed chiral forms activate at nanomolar concentration, 1 2 orders magnitude less than those S1PR3/5. Collectively, signify promise approach fine agonist G-protein-coupled receptors.

Language: Английский

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