ArticleCritical care (London, England)2009
VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis.
Article in Critical care (London, England), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Decoding Host-Pathogen Dynamics inAntibiotics (Basel, Switzerland) · 2026Review
- T-cell dysfunction and death in sepsis: a mechanistic review.Frontiers in immunology · 2026Review
- The Role of Inflammasomes in LPS and Gram-Negative Bacterial Sepsis.Journal of clinical medicine · 2025Review
- Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.Cellular & molecular biology letters · 2025Review
- The concealed side of caspases: beyond a killer of cells.Cellular and molecular life sciences : CMLS · 2024Review
- Caspase-8 in inflammatory diseases: a potential therapeutic target.Cellular & molecular biology letters · 2024Review
- Pyroptosis: the potential eye of the storm in adult-onset Still's disease.Inflammopharmacology · 2023Review
- Role of pyroptosis in hemostasis activation in sepsis.Frontiers in immunology · 2023Review
- Predicting the prognosis in patients with sepsis by a pyroptosis-related gene signature.Frontiers in immunology · 2022Article
- ICU and Sepsis: Role of Myeloid and Lymphocyte Immune Cells.Journal of oncology · 2022Review
- Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages.Nature communications · 2021Article
- A long way to go: caspase inhibitors in clinical use.Cell death & disease · 2021Review
- Association between miR-126, miR-21, inflammatory factors and T lymphocyte apoptosis in septic rats.Molecular and clinical oncology · 2021Article
- Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies.Journal of innate immunity · 2021Review
- The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review.Frontiers in immunology · 2021Review
- Sepsis: Inflammation Is a Necessary Evil.Frontiers in cell and developmental biology · 2019Review
- An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy.Journal of medicinal chemistry · 2016Review
- Caspase-8 inhibition represses initial human monocyte activation in septic shock model.Oncotarget · 2016Article
- Revisiting caspases in sepsis.Cell death & disease · 2014Review
- Therapeutic interventions in sepsis: current and anticipated pharmacological agents.British journal of pharmacology · 2014Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionPrevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.
methodsVX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP).
resultsVX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected.
conclusionsOur studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
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